Inhibitors of low molecular weight protein tyrosine phosphatase and uses thereof

ABSTRACT

Herein are provided, inter  alia , compounds capable of modulating the level of activity of low molecular weight protein tyrosine phosphatase (LMPTP) and methods of using the same. In embodiments, the compound has a structure according to Formula (I-A).

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.15/518,331 filed on Apr. 11, 2017 which was filed pursuant to 35 U.S.C.§ 371 as a United States National Phase Application of InternationalApplication No. PCT/US 15/55607 entitled “INHIBITORS OF LOW MOLECULARWEIGHT PROTEIN TYROSINE PHOSPHATASE AND USES THEREOF” filed Oct. 14,2015; which claims benefit of U.S. Patent Application No. 62/063,937,entitled “SMALL MOLECULE ALLOSTERIC INHIBITORS OF LOW MOLECULAR WEIGHTPROTEIN TYROSINE PHOSPHATASE AND USES OF SAME” filed on Oct. 14, 2014,all of which are hereby incorporated by reference in their entirety.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

This invention was made with government support under R03 DA033986awarded by the National Institutes of Health. The government has certainrights in the invention.

BACKGROUND OF THE INVENTION

Obesity is frequently complicated by a constellation of metabolic andcardiovascular anomalies, called the metabolic syndrome, whichsignificantly increases morbidity and mortality of affected individuals.Insulin resistance is an important component of the metabolic syndrome.Protein tyrosine phosphatases (PTPs) that regulate insulin signaling arein principle excellent therapeutic targets for insulin resistancesyndromes, including low molecular weight protein tyrosine phosphatase(LMPTP), encoded by the ACP1 gene. LMPTP is highly expressed in liver,muscle, adipocytes, heart and other tissues. There is strong in vitroand in vivo evidence that LMPTP is a negative regulator of insulinsignaling and a promising drug target in obesity and heart failure.Genetic association studies in humans support a negative role for LMPTPin insulin resistance and the metabolic complications of obesity. Invivo, partial knock-down of LMPTP expression by specific antisenseoligonucleotides (ASOs) led to improved glycemic and lipid profiles anddecreased insulin resistance in diet-induced obese C57BL/6 mice.Interestingly, anti-LMPTP ASOs did not induce any metabolic phenotype inlean mice. Additionally, global deletion of LMPTP in mice protected micefrom cardiac hypertrophy, fibrosis, and heart failure.

It has been estimated that every year in the U.S. more than 70 billiondollars are spent for the treatment of obesity-related conditions andalmost 300,000 deaths/year can be attributed to the complications ofobesity. Obese patients often show multiple metabolic and cardiovascularanomalies known as “the metabolic syndrome”, including glucoseintolerance, hyperlipidemia (especially high triglycerides with lowHDL), and hypertension.

BRIEF SUMMARY OF THE INVENTION

Herein are provided, inter alia, compounds capable of modulating thelevel of activity of low molecular weight protein tyrosine phosphatase(LMPTP) and methods of using the same.

In an aspect is provided a compound having the formula

-   -   or a pharmaceutically acceptable salt thereof.    -   X is independently N or CR⁷.    -   Y is independently N or CR⁸.    -   Z is independently a covalent bond, —O—, —NR⁹—, —NR⁹C(O)—,        —C(O)NR⁹—, —O—C(O)—, or —C(O)—O—.    -   L¹ is independently a bond, substituted or unsubstituted        alkylene, substituted or unsubstituted heteroalkylene,        substituted or unsubstituted cycloalkylene, substituted or        unsubstituted heterocycloalkylene, substituted or unsubstituted        arylene, or substituted or unsubstituted heteroarylene.    -   R¹ is independently hydrogen, —NR¹⁰R¹¹, —OR¹², substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl.    -   R² is independently hydrogen, substituted or unsubstituted        alkyl, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl.    -   R³ is independently hydrogen, halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³,        —OCX³ ₃, —OCHX³ ₂, —OCH₂X³, —CN, —SO_(n3)R¹⁶, —SO_(v3)NR¹³R¹⁴,        —NHC(O)NR¹³R¹⁴, —N(O)_(m3), —NR¹³R¹⁴, —C(O)R¹⁵, —C(O)—OR¹⁵,        —C(O)NR¹³R¹⁴, —OR¹⁶, —NR¹³SO₂R¹⁶, —NR¹³C(O)R¹⁵, —NR¹³C(O)OR¹⁵,        —NR¹³OR¹⁵, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl.    -   R⁴ is independently hydrogen, halogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴,        —OCX⁴ ₃, —OCHX⁴ ₂, —OCH₂X⁴, —CN, —SO_(n4)R²⁰, —SO_(v4)NR¹⁷R¹⁸,        —NHC(O)NR¹⁷R¹⁸, —N(O)_(m4), —NR¹⁷R¹⁸, —C(O)R¹⁹, —C(O)—OR¹⁹,        —C(O)NR¹⁷R¹⁸, —OR²⁰, —NR¹⁷SO₂R²⁰, —NR¹⁷C(O)R¹⁹, —NR¹⁷C(O)OR¹⁹,        —NR¹⁷OR¹⁹, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl.    -   R⁵ is independently hydrogen, halogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵,        —OCX⁵ ₃, —OCHX⁵ ₂, —OCH₂X⁵, —CN, —SO_(n5)R²⁴, —SO_(v5)NR²¹R²²,        —NHC(O)NR²¹R²², —N(O)_(m5), —NR²¹R²², —C(O)R²³, —C(O)—OR²³,        —C(O)NR²¹R²², —OR²⁴, —NR²¹SO₂R²⁴, —NR²¹C(O)R²³, —NR²¹C(O)OR²³,        —NR²¹OR²³, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl.    -   R⁶ is independently hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶,        —OCX⁶ ₃, —OCHX⁶ ₂, —OCH₂X⁶, —CN, —SO_(n6)R²⁸, —SO_(v6)NR²⁵R²⁶,        —NHC(O)NR²⁵R²⁶, —N(O)_(m6), —NR²⁵R²⁶, —C(O)R²⁷, —C(O)—OR²⁷,        —C(O)NR²⁵R²⁶, —OR²⁸, —NR²⁵SO₂R²⁸, —NR²⁵C(O)R²⁷, —NR²⁵C(O)OR²⁷,        —NR²⁵OR²⁷, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl.    -   Each of R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸,        R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, and R²⁸ is        independently hydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X,        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;        R⁶ and R⁷, R¹⁰ and R¹¹, R¹⁴ and R¹⁵, and R¹⁸ and R¹⁹        substituents bonded to the same nitrogen atom may optionally be        joined to form a substituted or unsubstituted heterocycloalkyl        or substituted or unsubstituted heteroaryl.    -   Each of X³, X⁴, X⁵, and X⁶ is independently —F, —Cl, —Br, or —I.    -   Each of m3, m4, m5, and m6 is independently 1 or 2.    -   Each of n3, n4, n5, and n6 is independently an integer from 0 to        3.    -   Each of v3, v4, v5, and v6 is independently 1 or 2.

In an aspect is provided a pharmaceutical composition including acompound described herein, or pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient.

In an aspect is provided a method of inhibiting low molecular weightprotein tyrosine phosphatase (LMPTP) activity including contacting thelow molecular weight protein tyrosine phosphatase (LMPTP) with acompound described herein.

In an aspect is provided a method of treating a disease or conditionassociated with low molecular weight protein tyrosine phosphatase(LMPTP) including administering to a subject in need thereof aneffective amount of a compound described herein. In embodiments, thedisease or condition is diabetes, heart disease, coronary arterydisease, hyperlipidemia, lipodystrophy, insulin resistance, rheumaticdisease, atherosclerosis, myocardial infarction, stroke, high bloodpressure (hypertension), obesity, elevated fasting plasma glucose, highserum triglycerides, elevated blood cholesterol, cardiac hypertrophy,heart failure (e.g., hypertrophy-induced heart failure), or metabolicsyndrome.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows localization of the gene-trap in the mouse Acp1 gene usedto generate an LMPTP knockout mouse. Exon 3 and exon 4 are alternativelyspliced to generate Lmptp-A and -B isoforms.

FIG. 1B shows PCR-based mouse genotyping using a forward primer located5′ to the gene-trap, a forward primer within the gene-trap, and areverse primer located 3′ to the gene-trap.

FIG. 1C shows RT-PCR with Lmptp primers on RNA extracted from the liverof a KO mouse and heterozygous and wild-type (WT) littermates.

FIG. 1D shows anti-Lmptp Western blot and control anti-tubulin blot ofliver lysates of a KO mouse and heterozygous and WT littermates.

FIGS. 2A-2D show that LMPTP KO decreases diabetes of obese mice. FIG. 2Ashows weight curves over the course of the HFD. FIG. 2B showsintraperitoneal glucose tolerance test (IPGTT) was performed on mice at2 months of age, prior to the start of the HFD. Mice were fastedovernight and injected with 1 g glucose/kg body weight, and bloodglucose levels were measured at the indicated times. FIG. 2C shows IPGTTwas performed on mice after 3 months HFD. FIG. 2D shows that fastingserum insulin levels were assessed by ELISA.

FIG. 3 shows that knockdown of Lmptp with antisense oligonucleotides(ASO) impairs adipogenesis of 3T3-L1 cells.

FIG. 4 shows that the LMPTP-A isoform dephosphorylates the IR.

FIG. 5 shows that ML400 (Compound D1) inhibits LMPTP with anuncompetitive mechanism of action.

FIG. 6 shows that an LMPTP inhibitor (Entry 41 of Table 2) increasesphosphorylation of the insulin receptor in HepG2 cells.

FIG. 7 shows that Compound D1 inhibits adipogenesis of 3T3-L1 cells.

FIG. 8 shows that treatment with Compound D1 improves glucose toleranceof obese mice.

FIG. 9 shows that treatment with Compound D1 does not affect kidneyfunction.

FIG. 10 shows that treatment with Compound D1 does not affect liverfunction.

FIG. 11 shows that an LMPTP inhibitor (Compound G53) binds to LMPTP byisothermal calorimetry.

FIG. 12 shows the stability of Compound D1 in 1×PBS and 1:1 PBS:ACN atroom temperature.

FIG. 13 shows mouse pharmacokinetics of Compound D1 after iv (5 mg/kg),ip (10 mg/kg) or po (30 mg/kg) dosing.

FIG. 14 shows dose response curves of Compound D1 in the LMPTP enzymeinhibition assays with OMFP and pNPP as substrates, as well as in theLYP-1 and VHR-1 phosphatase selectivity assays.

FIG. 15 describes an SAR strategy for the quinazolinone series.

FIG. 16 describes an SAR strategy for the quinoline series.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e., unbranched) or branchedcarbon chain (or carbon), or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include mono-, di- andmultivalent radicals, having the number of carbon atoms designated(i.e., C₁-C₁₀ means one to ten carbons). Alkyl is an uncyclized chain.Examples of saturated hydrocarbon radicals include, but are not limitedto, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl,isobutyl, sec-butyl, (cyclohexyl)methyl, homologs and isomers of, forexample, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Anunsaturated alkyl group is one having one or more double bonds or triplebonds. Examples of unsaturated alkyl groups include, but are not limitedto, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers. An alkoxy is an alkylattached to the remainder of the molecule via an oxygen linker (—O—).

The term “alkylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkyl, asexemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (oralkylene) group will have from 1 to 24 carbon atoms, with those groupshaving 10 or fewer carbon atoms being preferred herein. A “lower alkyl”or “lower alkylene” is a shorter chain alkyl or alkylene group,generally having eight or fewer carbon atoms. The term “alkenylene,” byitself or as part of another substituent, means, unless otherwisestated, a divalent radical derived from an alkene.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcombinations thereof, including at least one carbon atom and at leastone heteroatom selected from the group consisting of O, N, P, Si, and S,and wherein the nitrogen and sulfur atoms may optionally be oxidized,and the nitrogen heteroatom may optionally be quaternized. Theheteroatom(s) O, N, P, S, B, As, and Si may be placed at any interiorposition of the heteroalkyl group or at the position at which the alkylgroup is attached to the remainder of the molecule. Heteroalkyl is anuncyclized chain. Examples include, but are not limited to:—CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃,—CH₂—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃,—CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and —CN. Up totwo or three heteroatoms may be consecutive, such as, for example,—CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃.

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent, means, unless otherwise stated, a divalent radical derivedfrom heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—. As describedabove, heteroalkyl groups, as used herein, include those groups that areattached to the remainder of the molecule through a heteroatom, such as—C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and/or —SO₂R′. Where“heteroalkyl” is recited, followed by recitations of specificheteroalkyl groups, such as —NR′R″ or the like, it will be understoodthat the terms heteroalkyl and —NR′R″ are not redundant or mutuallyexclusive. Rather, the specific heteroalkyl groups are recited to addclarity. Thus, the term “heteroalkyl” should not be interpreted hereinas excluding specific heteroalkyl groups, such as —NR′R″ or the like.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, mean, unless otherwise stated, cyclicversions of“alkyl” and “heteroalkyl,” respectively. Cycloalkyl andheterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, aheteroatom can occupy the position at which the heterocycle is attachedto the remainder of the molecule. Examples of cycloalkyl include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a“heterocycloalkylene,” alone or as part of another substituent, means adivalent radical derived from a cycloalkyl and heterocycloalkyl,respectively.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “acyl” means, unless otherwise stated, —C(O)R where R is asubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent, which can be a single ring ormultiple rings (preferably from 1 to 3 rings) that are fused together(i.e., a fused ring aryl) or linked covalently. A fused ring aryl refersto multiple rings fused together wherein at least one of the fused ringsis an aryl ring. The term “heteroaryl” refers to aryl groups (or rings)that contain at least one heteroatom such as N, O, or S, wherein thenitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. Thus, the term “heteroaryl” includesfused ring heteroaryl groups (i.e., multiple rings fused togetherwherein at least one of the fused rings is a heteroaromatic ring). A5,6-fused ring heteroarylene refers to two rings fused together, whereinone ring has 5 members and the other ring has 6 members, and wherein atleast one ring is a heteroaryl ring. Likewise, a 6,6-fused ringheteroarylene refers to two rings fused together, wherein one ring has 6members and the other ring has 6 members, and wherein at least one ringis a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to tworings fused together, wherein one ring has 6 members and the other ringhas 5 members, and wherein at least one ring is a heteroaryl ring. Aheteroaryl group can be attached to the remainder of the moleculethrough a carbon or heteroatom. Non-limiting examples of aryl andheteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl,pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl,oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl,benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl,indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl,quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl,2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl,5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. Substituents for each of the above notedaryl and heteroaryl ring systems are selected from the group ofacceptable substituents described below. An “arylene” and a“heteroarylene,” alone or as part of another substituent, mean adivalent radical derived from an aryl and heteroaryl, respectively. Aheteroaryl group substituent may be —O— bonded to a ring heteroatomnitrogen.

Spirocyclic rings are two or more rings wherein adjacent rings areattached through a single atom. The individual rings within spirocyclicrings may be identical or different. Individual rings in spirocyclicrings may be substituted or unsubstituted and may have differentsubstituents from other individual rings within a set of spirocyclicrings. Possible substituents for individual rings within spirocyclicrings are the possible substituents for the same ring when not part ofspirocyclic rings (e.g. substituents for cycloalkyl or heterocycloalkylrings). Spirocylic rings may be substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heterocycloalkylene andindividual rings within a spirocyclic ring group may be any of theimmediately previous list, including having all rings of one type (e.g.all rings being substituted heterocycloalkylene wherein each ring may bethe same or different substituted heterocycloalkylene). When referringto a spirocyclic ring system, heterocyclic spirocyclic rings means aspirocyclic rings wherein at least one ring is a heterocyclic ring andwherein each ring may be a different ring. When referring to aspirocyclic ring system, substituted spirocyclic rings means that atleast one ring is substituted and each substituent may optionally bedifferent.

The symbol “˜˜” denotes the point of attachment of a chemical moiety tothe remainder of a molecule or chemical formula.

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom.

The term “alkylarylene” as an arylene moiety covalently bonded to analkylene moiety (also referred to herein as an alkylene linker). Inembodiments, the alkylarylene group has the formula:

An alkylarylene moiety may be substituted (e.g. with a substituentgroup) on the alkylene moiety or the arylene linker (e.g. at carbons 2,3, 4, or 6) with halogen, oxo, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂CH₃—SO₃H, —OSO₃H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted C₁-C₅ alkyl orsubstituted or unsubstituted 2 to 5 membered heteroalkyl). Inembodiments, the alkylarylene is unsubstituted.

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl,” and“heteroaryl”) includes both substituted and unsubstituted forms of theindicated radical. Preferred substituents for each type of radical areprovided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R″′, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R″′, —NR″C(O)₂R′, —NR—C(NR′R″R″′)═NR″″,—NR—C(NR′R″)═NR″′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R″′,—ONR′R″, —NR′C(O)NR″NR″′R″″, —CN, —NO₂, —NR′SO₂R″, —NR′C(O)R″,—NR′C(O)—OR″, —NR′OR″, in a number ranging from zero to (2m′+1), wherem′ is the total number of carbon atoms in such radical. R, R′, R″, R″′,and R″″ each preferably independently refer to hydrogen, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl (e.g., aryl substituted with 1-3 halogens),substituted or unsubstituted heteroaryl, substituted or unsubstitutedalkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When acompound described herein includes more than one R group, for example,each of the R groups is independently selected as are each R′, R″, R″′,and R″″ group when more than one of these groups is present. When R′ andR″ are attached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example,—NR′R″ includes, but is not limited to, 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups including carbon atoms bound to groups other than hydrogengroups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g.,—C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R″′,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R″′, —NR″C(O)₂R′, —NR—C(NR′R″R″′)═NR″″, —NR—C(NR′R″)═NR″′,—S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R″′, —ONR′R″,—NR′C(O)NR″NR″′R″″, —CN, —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy,and fluoro(C₁-C₄)alkyl, —NR′SO₂R″, —NR′C(O)R″, —NR′C(O)—OR″, —NR′OR″, ina number ranging from zero to the total number of open valences on thearomatic ring system; and where R′, R″, R″′, and R″″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl. When a compound described herein includes more than one Rgroup, for example, each of the R groups is independently selected asare each R′, R″, R″′, and R″″ groups when more than one of these groupsis present.

Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl,heteroaryl, cycloalkylene, heterocycloalkylene, arylene, orheteroarylene) may be depicted as substituents on the ring rather thanon a specific atom of a ring (commonly referred to as a floatingsubstituent). In such a case, the substituent may be attached to any ofthe ring atoms (obeying the rules of chemical valency) and in the caseof fused rings or spirocyclic rings, a substituent depicted asassociated with one member of the fused rings or spirocyclic rings (afloating substituent on a single ring), may be a substituent on any ofthe fused rings or spirocyclic rings (a floating substituent on multiplerings). When a substituent is attached to a ring, but not a specificatom (a floating substituent), and a subscript for the substituent is aninteger greater than one, the multiple substituents may be on the sameatom, same ring, different atoms, different fused rings, differentspirocyclic rings, and each substituent may optionally be different.Where a point of attachment of a ring to the remainder of a molecule isnot limited to a single atom (a floating substituent), the attachmentpoint may be any atom of the ring and in the case of a fused ring orspirocyclic ring, any atom of any of the fused rings or spirocyclicrings while obeying the rules of chemical valency. Where a ring, fusedrings, or spirocyclic rings contain one or more ring heteroatoms and thering, fused rings, or spirocyclic rings are shown with one more floatingsubstituents (including, but not limited to, points of attachment to theremainder of the molecule), the floating substituents may be bonded tothe heteroatoms. Where the ring heteroatoms are shown bound to one ormore hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and athird bond to a hydrogen) in the structure or formula with the floatingsubstituent, when the heteroatom is bonded to the floating substituent,the substituent will be understood to replace the hydrogen, whileobeying the rules of chemical valency.

Two or more substituents may optionally be joined to form aryl,heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-calledring-forming substituents are typically, though not necessarily, foundattached to a cyclic base structure. In one embodiment, the ring-formingsubstituents are attached to adjacent members of the base structure. Forexample, two ring-forming substituents attached to adjacent members of acyclic base structure create a fused ring structure. In anotherembodiment, the ring-forming substituents are attached to a singlemember of the base structure. For example, two ring-forming substituentsattached to a single member of a cyclic base structure create aspirocyclic structure. In yet another embodiment, the ring-formingsubstituents are attached to non-adjacent members of the base structure.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally form a ring of the formula -T-C(O)—(CRR′)_(q)—U—, whereinT and U are independently —NR—, —O—, —CRR′—, or a single bond, and q isan integer of from 0 to 3. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula -A-(CH₂)_(r)—B—, wherein A and B areindependently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′—, or asingle bond, and r is an integer of from 1 to 4. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —(CRR′)_(s)—X′—(C″R″R″′)_(d)—, where s and d are independentlyintegers of from 0 to 3, and X′ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R″, and R″′ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant toinclude oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), andsilicon (Si).

A “substituent group,” as used herein, means a group selected from thefollowing moieties:

-   -   (A) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,        —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,        —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃,        —OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl,        unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,        unsubstituted aryl, unsubstituted heteroaryl, and    -   (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, substituted with at least one substituent selected        from:        -   (i) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,            —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,            —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃,            —OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl,            unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,            unsubstituted aryl, unsubstituted heteroaryl, and        -   (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,            heteroaryl, substituted with at least one substituent            selected from:            -   (a) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,                —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,                —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H,                —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, unsubstituted alkyl,                unsubstituted heteroalkyl, unsubstituted cycloalkyl,                unsubstituted heterocycloalkyl, unsubstituted aryl,                unsubstituted heteroaryl, and            -   (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,                aryl, heteroaryl, substituted with at least one                substituent selected from: oxo, halogen, —CF₃, —CN, —OH,                —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,                —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,                —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,                unsubstituted alkyl, unsubstituted heteroalkyl,                unsubstituted cycloalkyl, unsubstituted                heterocycloalkyl, unsubstituted aryl, unsubstituted                heteroaryl.

In some embodiments, each substituted group described in the compoundsherein is substituted with at least one substituent group. Morespecifically, in some embodiments, each substituted alkyl, substitutedheteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl,substituted aryl, substituted heteroaryl, substituted alkylene,substituted heteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substitutedheteroarylene described in the compounds herein are substituted with atleast one substituent group. In other embodiments, at least one or allof these groups are substituted with at least one size-limitedsubstituent group. In other embodiments, at least one or all of thesegroups are substituted with at least one lower substituent group.

In other embodiments of the compounds herein, each substituted orunsubstituted alkyl may be a substituted or unsubstituted C₁-C₂₀ alkyl,each substituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl. In someembodiments of the compounds herein, each substituted or unsubstitutedalkylene is a substituted or unsubstituted C₁-C₂₀ alkylene, eachsubstituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 20 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₈cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 8 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 10 membered heteroarylene.

In some embodiments, each substituted or unsubstituted alkyl is asubstituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and/or each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl. In some embodiments, each substituted orunsubstituted alkylene is a substituted or unsubstituted C₁-C₈ alkylene,each substituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 8 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₇cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 7 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 9 membered heteroarylene. In someembodiments, the compound is a chemical species set forth in theExamples section, figures, or tables below.

Certain compounds of the present invention possess asymmetric carbonatoms (optical or chiral centers) or double bonds; the enantiomers,racemates, diastereomers, tautomers, geometric isomers, stereoisometricforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers areencompassed within the scope of the present invention. The compounds ofthe present invention do not include those that are known in art to betoo unstable to synthesize and/or isolate. The present invention ismeant to include compounds in racemic and optically pure forms.Optically active (R)- and (S)-, or (D)- and (L)-isomers may be preparedusing chiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic bondsor other centers of geometric asymmetry, and unless specified otherwise,it is intended that the compounds include both E and Z geometricisomers.

As used herein, the term “isomers” refers to compounds having the samenumber and kind of atoms, and hence the same molecular weight, butdiffering in respect to the structural arrangement or configuration ofthe atoms.

The term “tautomer,” as used herein, refers to one of two or morestructural isomers which exist in equilibrium and which are readilyconverted from one isomeric form to another.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areencompassed within the scope of the present invention.

It should be noted that throughout the application that alternatives arewritten in Markush groups, for example, each amino acid position thatcontains more than one possible amino acid. It is specificallycontemplated that each member of the Markush group should be consideredseparately, thereby comprising another embodiment, and the Markush groupis not to be read as a single unit.

“Analog,” or “analogue” is used in accordance with its plain ordinarymeaning within Chemistry and Biology and refers to a chemical compoundthat is structurally similar to another compound (i.e., a so-called“reference” compound) but differs in composition, e.g., in thereplacement of one atom by an atom of a different element, or in thepresence of a particular functional group, or the replacement of onefunctional group by another functional group, or the absolutestereochemistry of one or more chiral centers of the reference compound.Accordingly, an analog is a compound that is similar or comparable infunction and appearance but not in structure or origin to a referencecompound.

The terms “a” or “an,” as used in herein means one or more. In addition,the phrase “substituted with a[n],” as used herein, means the specifiedgroup may be substituted with one or more of any or all of the namedsubstituents. For example, where a group, such as an alkyl or heteroarylgroup, is “substituted with an unsubstituted C₁-C₂₀ alkyl, orunsubstituted 2 to 20 membered heteroalkyl,” the group may contain oneor more unsubstituted C₁-C₂₀ alkyls, and/or one or more unsubstituted 2to 20 membered heteroalkyls.

Moreover, where a moiety is substituted with an R substituent, the groupmay be referred to as “R-substituted.” Where a moiety is R-substituted,the moiety is substituted with at least one R substituent and each Rsubstituent is optionally different. Where a particular R group ispresent in the description of a chemical genus (such as Formula (I)), aRoman alphabetic symbol may be used to distinguish each appearance ofthat particular R group. For example, where multiple R¹³ substituentsare present, each R¹³ substituent may be distinguished asR^(13A)R^(13B), R^(13C), R^(13D), etc., wherein each of R^(13A),R^(13B), R^(13C), R^(13D), etc. is defined within the scope of thedefinition of R¹³ and optionally differently.

Description of compounds of the present invention are limited byprinciples of chemical bonding known to those skilled in the art.Accordingly, where a group may be substituted by one or more of a numberof substituents, such substitutions are selected so as to comply withprinciples of chemical bonding and to give compounds which are notinherently unstable and/or would be known to one of ordinary skill inthe art as likely to be unstable under ambient conditions, such asaqueous, neutral, and several known physiological conditions. Forexample, a heterocycloalkyl or heteroaryl is attached to the remainderof the molecule via a ring heteroatom in compliance with principles ofchemical bonding known to those skilled in the art thereby avoidinginherently unstable compounds.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds that are prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and thelike. Also included are salts of amino acids such as arginate and thelike, and salts of organic acids like glucuronic or galactunoric acidsand the like (see, for example, Berge et al., “Pharmaceutical Salts”,Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specificcompounds of the present invention contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

Thus, the compounds of the present invention may exist as salts, such aswith pharmaceutically acceptable acids. The present invention includessuch salts. Non-limiting examples of such salts include hydrochlorides,hydrobromides, phosphates, sulfates, methanesulfonates, nitrates,maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g.,(+)-tartrates, (−)-tartrates, or mixtures thereof including racemicmixtures), succinates, benzoates, and salts with amino acids such asglutamic acid, and quaternary ammonium salts (e.g. methyl iodide, ethyliodide, and the like). These salts may be prepared by methods known tothose skilled in the art.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compound maydiffer from the various salt forms in certain physical properties, suchas solubility in polar solvents.

In addition to salt forms, the present invention provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Prodrugs of the compounds described herein may be convertedin vivo after administration. Additionally, prodrugs can be converted tothe compounds of the present invention by chemical or biochemicalmethods in an ex vivo environment, such as, for example, when contactedwith a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of an activeagent to and absorption by a subject and can be included in thecompositions of the present invention without causing a significantadverse toxicological effect on the patient. Non-limiting examples ofpharmaceutically acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors, salt solutions (such as Ringer's solution), alcohols, oils,gelatins, carbohydrates such as lactose, amylose or starch, fatty acidesters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, andthe like. Such preparations can be sterilized and, if desired, mixedwith auxiliary agents such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, and/or aromatic substances and the like that do notdeleteriously react with the compounds of the invention. One of skill inthe art will recognize that other pharmaceutical excipients are usefulin the present invention.

The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

A “low molecular weight protein tyrosine phosphatase (LMPTP) inhibitor”or “LMPTP compound” or “LMPTP inhibitor” refers to a compound (e.g.compounds described herein) that reduces the activity of low molecularweight protein tyrosine phosphatase (LMPTP).”

“Contacting” is used in accordance with its plain ordinary meaning andrefers to the process of allowing at least two distinct species (e.g.chemical compounds including biomolecules or cells) to becomesufficiently proximal to react, interact or physically touch. It shouldbe appreciated; however, the resulting reaction product can be produceddirectly from a reaction between the added reagents or from anintermediate from one or more of the added reagents that can be producedin the reaction mixture.

The term “contacting” may include allowing two species to react,interact, or physically touch, wherein the two species may be a compoundas described herein and a protein or enzyme. In some embodimentscontacting includes allowing a compound described herein to interactwith a protein or enzyme that is involved in a signaling pathway.

As defined herein, the term “activation”, “activate”, “activating” andthe like in reference to a protein refers to conversion of a proteininto a biologically active derivative from an initial inactive ordeactivated state. The terms reference activation, or activating,sensitizing, or up-regulating signal transduction or enzymatic activityor the amount of a protein decreased in a disease.

As defined herein, the term “inhibition”, “inhibit”, “inhibiting” andthe like in reference to a protein-inhibitor interaction meansnegatively affecting (e.g. decreasing) the activity or function of theprotein relative to the activity or function of the protein in theabsence of the inhibitor. In embodiments inhibition means negativelyaffecting (e.g. decreasing) the concentration or levels of the proteinrelative to the concentration or level of the protein in the absence ofthe inhibitor. In embodiments, inhibition refers to reduction of adisease or symptoms of disease. In embodiments, inhibition refers to areduction in the activity of a particular protein target. Thus,inhibition includes, at least in part, partially or totally blockingstimulation, decreasing, preventing, or delaying activation, orinactivating, desensitizing, or down-regulating signal transduction orenzymatic activity or the amount of a protein. In embodiments,inhibition refers to a reduction of activity of a target proteinresulting from a direct interaction (e.g. an inhibitor binds to thetarget protein). In embodiments, inhibition refers to a reduction ofactivity of a target protein from an indirect interaction (e.g. aninhibitor binds to a protein that activates the target protein, therebypreventing target protein activation). A “low molecular weight proteintyrosine phosphatase (LMPTP) inhibitor” and “LMPTP inhibitor” is acompound that negatively affects (e.g. decreases) the activity orfunction of low molecular weight protein tyrosine phosphatase (LMPTP)relative to the activity or function of low molecular weight proteintyrosine phosphatase (LMPTP) in the absence of the inhibitor (e.g.,wherein the LMPTP inhibitor binds LMPTP).

In embodiments, the low molecular weight protein tyrosine phosphatase(LMPTP) inhibitor is an allosteric inhibitor. As used herein, anallosteric inhibitor binds to an allosteric site other than the activesite of the LMPTP, thereby inhibiting activity of the LMPTP.

The terms “low molecular weight protein tyrosine phosphatase” and“LMPTP” refer to a protein (including homologs, isoforms, and functionalfragments thereof) with low molecular weight protein tyrosinephosphatase (LMPTP). The term includes any recombinant ornaturally-occurring form of low molecular weight protein tyrosinephosphatase (LMPTP) or variants thereof that maintain low molecularweight protein tyrosine phosphatase (LMPTP) (e.g. within at least 30%,40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtypelow molecular weight protein tyrosine phosphatase (LMPTP)). Inembodiments, the LMPTP is a human LMPTP.

The terms “disease” or “condition” refer to a state of being or healthstatus of a patient or subject capable of being treated with thecompounds or methods provided herein. In embodiments, the disease orcondition is diabetes, heart disease, coronary artery disease,hyperlipidemia, lipodystrophy, insulin resistance, rheumatic disease,atherosclerosis, myocardial infarction, stroke, high blood pressure(hypertension), obesity, elevated fasting plasma glucose, high serumtriglycerides, elevated blood cholesterol, cardiac hypertrophy, heartfailure (e.g., hypertrophy-induced heart failure), or metabolicsyndrome.

The term “obesity” is generally defined as a body mass index (BMI) over30, for purposes of this disclosure, any subject, including those with abody mass index of less than 30, who needs or wishes to reduce bodyweight or prevent body weight gain is included in the scope of “obese.”Thus, subjects with a BMI of less than 30 and 25 and above (consideredoverweight) or below 25 are also included in the subjects of theinvention. Morbid obesity refers to a BMI of 40 or greater.

In embodiments, the disease or condition is a metabolic disease ordisorder including those which can be alleviated by control of plasmaglucose levels, insulin levels, and/or insulin secretion, such asdiabetes and diabetes-related conditions, and conditions and disordersincluding, but not limited to, hypertension, dyslipidemia,cardiovascular or heart disease, eating disorders, insulin-resistance,obesity, and diabetes mellitus of any kind, including type 1, type 2,and gestational diabetes.

By “metabolic syndrome” is meant that a subject has a conditioncharacterized by at least two of increased triglycerides, reducedhigh-density lipoprotein (HDL), increased blood pressure, increasedfasting plasma glucose or type 2 diabetes, or obesity.

By “cardiac hypertrophy” is meant any undesirable cardiac muscle growth,increase in cardiac chamber mass relative to body size, or increase incardiac chamber wall thickness at normal or increased chamber volume.

The terms “heart disease” and “cardiovascular disease” refers to adisorder of the heart and blood vessels, and includes disorders of thearteries, veins, arterioles, venules, and capillaries. Heart diseaseincludes: atherosclerosis; autoimmune myocarditis, chronic cardiachypoxia, congestive heart failure, coronary artery disease,cardiomyopathy and cardiac cell dysfunction (e.g., aortic smooth musclecell activation; cardiac cell apoptosis; and immunomodulation of cardiaccell function).

The terms “treating”, or “treatment” refers to any indicia of success inthe therapy or amelioration of an injury, disease, pathology orcondition, including any objective or subjective parameter such asabatement; remission; diminishing of symptoms or making the injury,pathology or condition more tolerable to the patient; slowing in therate of degeneration or decline; making the final point of degenerationless debilitating; improving a patient's physical or mental well-being.The treatment or amelioration of symptoms can be based on objective orsubjective parameters; including the results of a physical examination,neuropsychiatric exams, and/or a psychiatric evaluation. The term“treating” and conjugations thereof, may include prevention of aninjury, pathology, condition, or disease.

“Patient” or “subject in need thereof” refers to a living organismsuffering from or prone to a disease or condition that can be treated byadministration of a pharmaceutical composition as provided herein.Non-limiting examples include humans, other mammals, bovines, rats,mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammaliananimals. In some embodiments, a patient is human.

A “effective amount” is an amount sufficient for a compound toaccomplish a stated purpose relative to the absence of the compound(e.g. achieve the effect for which it is administered, treat a disease,reduce enzyme activity, increase enzyme activity, reduce a signalingpathway, or reduce one or more symptoms of a disease or condition). Anexample of an “effective amount” is an amount sufficient to contributeto the treatment, prevention, or reduction of a symptom or symptoms of adisease, which could also be referred to as a “therapeutically effectiveamount.” A “reduction” of a symptom or symptoms (and grammaticalequivalents of this phrase) means decreasing of the severity orfrequency of the symptom(s), or elimination of the symptom(s). A“prophylactically effective amount” of a drug is an amount of a drugthat, when administered to a subject, will have the intendedprophylactic effect, e.g., preventing or delaying the onset (orreoccurrence) of an injury, disease, pathology or condition, or reducingthe likelihood of the onset (or reoccurrence) of an injury, disease,pathology, or condition, or their symptoms. The full prophylactic effectdoes not necessarily occur by administration of one dose, and may occuronly after administration of a series of doses. Thus, a prophylacticallyeffective amount may be administered in one or more administrations. An“activity decreasing amount,” as used herein, refers to an amount ofantagonist required to decrease the activity of an enzyme relative tothe absence of the antagonist. A “function disrupting amount,” as usedherein, refers to the amount of antagonist required to disrupt thefunction of an enzyme or protein relative to the absence of theantagonist. The exact amounts will depend on the purpose of thetreatment, and will be ascertainable by one skilled in the art usingknown techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms(vols. 1-3, 1992); Lloyd, The Art, Science and Technology ofPharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999);and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003,Gennaro, Ed., Lippincott, Williams & Wilkins).

For any compound described herein, the therapeutically effective amountcan be initially determined from cell culture assays. Targetconcentrations will be those concentrations of active compound(s) thatare capable of achieving the methods described herein, as measured usingthe methods described herein or known in the art.

As is well known in the art, therapeutically effective amounts for usein humans can also be determined from animal models. For example, a dosefor humans can be formulated to achieve a concentration that has beenfound to be effective in animals. The dosage in humans can be adjustedby monitoring compounds effectiveness and adjusting the dosage upwardsor downwards, as described above. Adjusting the dose to achieve maximalefficacy in humans based on the methods described above and othermethods is well within the capabilities of the ordinarily skilledartisan.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the present invention should be sufficient to affect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side-effects. Determination of the proper dosage for aparticular situation is within the skill of the practitioner. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances isreached. Dosage amounts and intervals can be adjusted individually toprovide levels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

As used herein, the term “administering” means oral administration,administration as a suppository, topical contact, intravenous,intraperitoneal, intramuscular, intralesional, intrathecal, intranasalor subcutaneous administration, or the implantation of a slow-releasedevice, e.g., a mini-osmotic pump, to a subject. Administration is byany route, including parenteral and transmucosal (e.g., buccal,sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal)compatible with the preparation. Parenteral administration includes,e.g., intravenous, intramuscular, intra-arteriole, intradermal,subcutaneous, intraperitoneal, intraventricular, and intracranial. Othermodes of delivery include, but are not limited to, the useof^(liposomal) formulations, intravenous infusion, transdermal patches,etc.

As used herein, the term “Co-administer” means that a compositiondescribed herein is administered at the same time, just prior to, orjust after the administration of one or more additional therapies. Thecompounds of the invention can be administered alone or can beco-administered to the patient. Co-administration is meant to includesimultaneous or sequential administration of the compounds individuallyor in combination (more than one compound). Thus, the preparations canalso be combined, when desired, with other active substances (e.g. toreduce metabolic degradation). The compositions of the present inventioncan be delivered transdermally, by a topical route, or formulated asapplicator sticks, solutions, suspensions, emulsions, gels, creams,ointments, pastes, jellies, paints, powders, and aerosols.

A “cell” as used herein, refers to a cell carrying out metabolic orother function sufficient to preserve or replicate its genomic DNA. Acell can be identified by well-known methods in the art including, forexample, presence of an intact membrane, staining by a particular dye,ability to produce progeny or, in the case of a gamete, ability tocombine with a second gamete to produce a viable offspring. Cells mayinclude prokaryotic and eukaryotic cells. Prokaryotic cells include butare not limited to bacteria. Eukaryotic cells include but are notlimited to yeast cells and cells derived from plants and animals, forexample mammalian, insect (e.g., spodoptera) and human cells. Cells maybe useful when they are naturally nonadherent or have been treated notto adhere to surfaces, for example by trypsinization.

“Control” or “control experiment” is used in accordance with its plainordinary meaning and refers to an experiment in which the subjects orreagents of the experiment are treated as in a parallel experimentexcept for omission of a procedure, reagent, or variable of theexperiment. In some instances, the control is used as a standard ofcomparison in evaluating experimental effects. In some embodiments, acontrol is the measurement of the activity of a protein in the absenceof a compound as described herein (including embodiments and examples).

The term “modulator” refers to a composition that increases or decreasesthe level of a target molecule or the function of a target molecule orthe physical state of the target of the molecule. In some embodiments, alow molecular weight protein tyrosine phosphatase (LMPTP) associateddisease modulator is a compound that reduces the severity of one or moresymptoms of a disease associated with low molecular weight proteintyrosine phosphatase (LMPTP). A low molecular weight protein tyrosinephosphatase (LMPTP) modulator is a compound that increases or decreasesthe activity or function or level of activity or level of function oflow molecular weight protein tyrosine phosphatase (LMPTP).

The term “modulate” is used in accordance with its plain ordinarymeaning and refers to the act of changing or varying one or moreproperties. “Modulation” refers to the process of changing or varyingone or more properties. For example, as applied to the effects of amodulator on a target protein, to modulate means to change by increasingor decreasing a property or function of the target molecule or theamount of the target molecule.

The term “associated” or “associated with” in the context of a substanceor substance activity or function associated with a disease (e.g. aprotein associated disease, a cancer associated with low molecularweight protein tyrosine phosphatase (LMPTP) activity or a low molecularweight protein tyrosine phosphatase (LMPTP) associated disease orcondition) means that the disease is caused by (in whole or in part), ora symptom of the disease is caused by (in whole or inpart) the substanceor substance activity or function. For example, a disease or conditionassociated with low molecular weight protein tyrosine phosphatase(LMPTP) activity or function may be one that results (entirely orpartially) from aberrant low molecular weight protein tyrosinephosphatase (LMPTP) function (e.g. enzyme activity, protein-proteininteraction, signaling pathway) or a disease or condition wherein aparticular symptom of the disease or condition is caused (entirely orpartially) by aberrant low molecular weight protein tyrosine phosphatase(LMPTP) activity or function. As used herein, what is described as beingassociated with a disease, if a causative agent, could be a target fortreatment of the disease. For example, a disease or condition associatedwith low molecular weight protein tyrosine phosphatase (LMPTP) activityor function or a low molecular weight protein tyrosine phosphatase(LMPTP) associated disease or condition, may be treated with a lowmolecular weight protein tyrosine phosphatase (LMPTP) modulator or lowmolecular weight protein tyrosine phosphatase (LMPTP) inhibitor, in theinstance where increased low molecular weight protein tyrosinephosphatase (LMPTP) activity or function causes the disease orcondition.

The term “aberrant” as used herein refers to different from normal. Whenused to describe enzymatic activity or protein function, aberrant refersto activity or function that is greater or less than a normal control orthe average of normal non-diseased control samples. Aberrant activitymay refer to an amount of activity that results in a disease, whereinreturning the aberrant activity to a normal or non-disease-associatedamount (e.g. by administering a compound or using a method as describedherein), results in reduction of the disease or one or more diseasesymptoms.

The term “signaling pathway” as used herein refers to a series ofinteractions between cellular and optionally extra-cellular components(e.g. proteins, nucleic acids, small molecules, ions, lipids) thatconveys a change in one component to one or more other components, whichin turn may convey a change to additional components, which isoptionally propagated to other signaling pathway components. Forexample, binding of a low molecular weight protein tyrosine phosphatase(LMPTP) with a compound as described herein may reduce the level of aproduct of the low molecular weight protein tyrosine phosphatase (LMPTP)catalyzed reaction or the level of a downstream derivative of theproduct or binding may reduce the interactions between the low molecularweight protein tyrosine phosphatase (LMPTP) enzyme or a low molecularweight protein tyrosine phosphatase (LMPTP) reaction product anddownstream effectors or signaling pathway components, resulting inchanges in cell growth, proliferation, or survival.

II. Compounds

Disclosed herein is a collection of small-molecule inhibitors of the lowmolecular weight protein tyrosine phosphatase (LMPTP). The assaysutilized in the primary and secondary screening were designed toidentify allosteric inhibitors of LMPTP. All of these compounds inhibitLMPTP in vitro, and show poor inhibition of two other protein tyrosinephosphatases, the lymphoid phosphatase (LYP) and the VH1-relatedphosphatase (VHR). The structure of the compounds was further optimizedto generate a series of inhibitors of LMPTP-A isoform, with highselectivity over the LMPTP-B isoform, LYP and VHR, and with cellularactivity. In an aspect is provided a compound having the formula:

-   -   or a pharmaceutically acceptable salt thereof.    -   X is independently N or CR⁷.    -   Y is independently N or CR⁸.    -   Z is independently a covalent bond, —O—, —NR⁹—, —NR⁹C(O)—,        —C(O)NR⁹—, —O—C(O)—, or —C(O)—O—.    -   L¹ is independently a bond, substituted or unsubstituted        alkylene, substituted or unsubstituted heteroalkylene,        substituted or unsubstituted cycloalkylene, substituted or        unsubstituted heterocycloalkylene, substituted or unsubstituted        arylene, or substituted or unsubstituted heteroarylene.    -   R¹ is independently hydrogen, —NR¹⁰R¹¹, —OR¹², substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl.    -   R² is independently hydrogen, —OR^(2B), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl.    -   R³ is independently hydrogen, halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³,        —OCX³ ₃, —OCHX³ ₂, —OCH₂X³, —CN, —SO_(n3)R¹⁶, —SO_(v3)NR¹³R¹⁴,        —NHC(O)NR¹³R¹⁴, —N(O)_(m3), —NR¹³R¹⁴, —C(O)R¹⁵, —C(O)—OR¹⁵,        —C(O)NR¹³R¹⁴, —OR¹⁶, —NR¹³SO₂R¹⁶, —NR¹³C(O)R¹⁵, —NR¹³C(O)OR¹⁵,        —NR¹³OR¹⁵, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl.    -   R⁴ is independently hydrogen, halogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴,        —OCX⁴ ₃, —OCHX⁴ ₂, —OCH₂X⁴, —CN, —SO_(n4)R²⁰, —SO_(v4)NR¹⁷R¹⁸,        —NHC(O)NR¹⁷R¹⁸, —N(O)_(m4), —NR¹⁷R¹⁸, —C(O)R¹⁹, —C(O)—OR¹⁹,        —C(O)NR¹⁷R¹⁸, —OR²⁰, —NR¹⁷SO₂R²⁰, —NR¹⁷C(O)R¹⁹, —NR¹⁷C(O)OR¹⁹,        —NR¹⁷OR¹⁹, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl.    -   R⁵ is independently hydrogen, halogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵,        —OCX⁵ ₃, —OCHX⁵ ₂, —OCH₂X⁵, —CN, —SO_(n5)R²⁴, —SO_(v5)NR²¹R²²,        —NHC(O)NR²¹R²², —N(O)_(m5), —NR²¹R²², —C(O)R²³, —C(O)—OR²³,        —C(O)NR²¹R²², —OR²⁴, —NR²¹SO₂R²⁴, —NR²¹C(O)R²³, —NR²¹C(O)OR²³,        —NR²¹OR²³, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl.    -   R⁶ is independently hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶,        —OCX⁶ ₃, —OCHX⁶ ₂, —OCH₂X⁶, —CN, —SO_(n6)R²⁸, —SO_(v6)NR²⁵R²⁶,        —NHC(O)NR²⁵R²⁶, —N(O)_(m6), —NR²⁵R²⁶, —C(O)R²⁷, —C(O)—OR²⁷,        —C(O)NR²⁵R²⁶, —OR²⁸, —NR²⁵SO₂R²⁸, —NR²⁵C(O)R²⁷, —NR²⁵C(O)OR²⁷,        —NR²⁵OR²⁷, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl.    -   R^(2B) is independently hydrogen, substituted or unsubstituted        alkyl, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl.    -   Each of R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸,        R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, and R²⁸ is        independently hydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X,        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;        R⁶ and R⁷, R¹⁰ and R¹¹, R¹⁴ and R¹⁵, and R¹⁸ and R¹⁹        substituents bonded to the same nitrogen atom may optionally be        joined to form a substituted or unsubstituted heterocycloalkyl        or substituted or unsubstituted heteroaryl.    -   Each of X³, X⁴, X⁵, and X⁶ is independently —F, —Cl, —Br, or —I.    -   Each of m3, m4, m5, and m6 is independently 1 or 2.    -   Each of n3, n4, n5, and n6 is independently an integer from 0 to        3.    -   Each of v3, v4, v5, and v6 is independently 1 or 2.

In embodiments X is independently N. In embodiments, X is independentlyCR⁷.

In embodiments, Y is independently N. In embodiments, Y is independentlyCR⁸.

In embodiments, X is N, and Y is CR⁸. In embodiments, X and Y are eachN.

In embodiments, the compound has a structure according to formula (I-A).

In embodiments, the compound has a structure according to formula (I-B).

In embodiments, when X and Y are each N, Z is —NH—, R³-R⁶ are eachhydrogen, L¹ is substituted or unsubstituted C₁₋₃ alkylene, and R² isunsubstituted morpholine, unsubstituted pyridine, unsubstituted phenyl,unsubstituted imidazole, unsubstituted tetrahydrofuran, unsubstitutedcyclopentane, or dimethoxybenzene, then R¹ is not —C₆H₅, 3-CH₃C₆H₄,4-CH₃C₆H₄, 2-FC₆H₄, or 4-O^(i)PrC₆H₄. In embodiments, when X and Y areeach N, Z is —NH—, R³-R⁶ are each hydrogen, L¹ is substituted orunsubstituted C₁₋₆ alkylene, and R² is unsubstituted morpholine,unsubstituted pyridine, unsubstituted phenyl, unsubstituted imidazole,unsubstituted tetrahydrofuran, unsubstituted cyclopentane, ordimethoxybenzene, then R¹ is not —C₆H₅, 3-CH₃C₆H₄, 4-CH₃C₆H₄, 2-FC₆H₄,or 4-O^(i)PrC₆H₄. In embodiments, when X and Y are each N, Z is —NH—,R³-R⁶ are each hydrogen, L¹ is substituted or unsubstituted C₁₋₆alkylene, R² is unsubstituted morpholine, unsubstituted pyridine,unsubstituted phenyl, unsubstituted imidazole, unsubstitutedtetrahydrofuran, unsubstituted cyclopentane, or dimethoxybenzene, and R¹is aryl, then R¹ is not unsubstituted phenyl or a phenyl groupsubstituted only by 1 or 2 groups selected from halogen, unsubstitutedalkyl, or unsubstituted alkoxy. In embodiments, when X and Y are each N,Z is —NH—, R³-R⁶ are each hydrogen, L¹ is substituted or unsubstitutedC₁₋₆ alkylene (e.g., unsubstituted C₁₋₃ alkylene), R² is unsubstitutedmorpholine, unsubstituted pyridine, unsubstituted phenyl, unsubstitutedimidazole, unsubstituted tetrahydrofuran, unsubstituted cyclopentane, ordimethoxybenzene, and R¹ is aryl (e.g., phenyl), then R₁ comprises anamide substituent (e.g., —C(O)NR^(1C)R^(1D) as described herein).

In embodiments, when X and Y are each N, Z is NH, R³-R⁶ are eachhydrogen, L¹ is a bond, and R² is —C₆H₄CO₂H or unsubstitutedcyclopentane, then R¹ is not unsubstituted phenyl or 4-NO₂C₆H₄. Inembodiments, when X and Y are each N, Z is NH, R³-R⁶ are each hydrogen,L¹ is a bond or substituted or unsubstituted alkylene, and R² is—C₆H₄CO₂H or unsubstituted cyclopentane, then R¹ is not unsubstitutedphenyl or 4-NO₂C₆H₄. In embodiments, when X and Y are each N, Z is NH,R³-R⁶ are each hydrogen, L¹ is a bond or substituted or unsubstitutedalkylene, and R² is —C₆H₄CO₂H or unsubstituted cyclopentane, and R¹ isphenyl, then R¹ comprises two or more substituents.

In embodiments, when X and Y are each N, Z is NH, R³-R⁶ are eachhydrogen, and -L¹-R² is —(CH₂)₃O(^(i)Pr), —(CH₂)₆CO₂H, or—(CH₂)₃OCH₂CH₃, then R¹ is not unsubstituted phenyl. In embodiments,when X and Y are each N, Z is NH, R³-R⁶ are each hydrogen, -L¹-R² is—(CH₂)₃O(^(i)Pr), —(CH₂)₆CO₂H, or —(CH₂)₃OCH₂CH₃, and R¹ is phenyl, thenR¹ comprises 2 or more substituents. In embodiments, when X and Y areeach N, Z is NH, R³-R⁶ are each hydrogen, -L¹-R² combine to form anunsubstituted heteroalkylene, and R¹ is phenyl, then R¹ comprises 1 ormore (e.g., 1 or more or 2 or more) substituents. In embodiments, when Xand Y are each N, Z is NH, R³-R⁶ are each hydrogen, -L¹-R² combine toform an alkyl having a carboxylic acid or carboxylic ester substituent,and R¹ is phenyl, then R¹ comprises 1 or more (e.g., 1 or more or 2 ormore) substituents.

In embodiments, when X is N, Y is CH, R³-R⁶ are each H, and —Z-L¹-R² is

(—NH(CH₂)₂N(CH₂)₅) or

(—N(CH₂)₅), then R¹ is not unsubstituted phenyl. In embodiments, when Xis N, Y is CH, R³-R⁶ are each H, and R² is unsubstituted piperidine,then R¹ is not unsubstituted phenyl. In embodiments, when X is N, Y isCH, R³-R⁶ are each H, and R² is unsubstituted piperidine, then R¹ is notunsubstituted phenyl. In embodiments, when X is N, Y is CH, R³-R⁶ areeach H, R² is unsubstituted piperidine, and R¹ is aryl (e.g., phenyl),then R₁ comprises an amide substituent (e.g., —C(O)NR^(1C)R^(1D) asdescribed herein).

In embodiments, Z is a bond, —O—, or —NR⁹—.

In embodiments, Z is —NH—, L¹ is substituted or unsubstituted C₁-C₆alkylene, and R² is selected from:

wherein a1 is 0, 1, 2, or 3; and R^(2B) is independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

In embodiments, —Z-L¹-R² is selected from:

wherein a1 is 0, 1, 2, or 3; b1 is 0, 1, or 2; and R^(2B) isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, —Z-L¹-R² is —C(O)NR^(2B)R^(2C) or —C(O)OR².

In embodiments, R¹ is unsubstituted phenyl. In embodiments, R¹ is phenylcomprising substituents (e.g., 1, 2, 3, 4 or 5 substituents) selectedfrom F, Cl, Br, —CN, —NR₄R₅, —NO₂, —CF₃, —OCF₃, —OH, substituted orunsubstituted C₁-C₆alkyl, and —O(substituted or unsubstitutedC₁-C₆alkyl). In embodiments, R¹ is -(substituted or unsubstitutedC₁-C₆alkyl)(O)(CF₃), -(substituted or unsubstitutedC₁-C₆alkyl)(O)-(substituted or unsubstituted C₁-C₆alkyl), -(substitutedor unsubstituted C₁-C₆alkyl) NH (substituted or unsubstitutedC₁-C₆alkyl), -(substituted or unsubstituted C₁-C₆alkyl) NR^(1B)R^(1C),—C(═O) (substituted or unsubstituted C₁-C₆alkyl), (substituted orunsubstituted cycloalkyl)-C₁-C₆alkyl, CO₂H, —C(═O)—O—R^(1B), C(═O)NH₂,C(═O)NR^(1B)R^(1C), or two groups on adjacent carbon atoms of the phenylgroup are combined with the adjacent carbon atoms to form a—O(CH₂)_(c1)O— ring. In embodiments, R¹ isC(═O)[(CH₂)_(d1)]NR^(1B)R^(1C), C(═O)[(CH₂)_(d1)]piperidine,C(═O)[(CH₂)_(d1)] morpholine, or C(═O)[(CH₂)_(d1)]piperazine, wherein d1is 0, 1, 2, 3, 4, 5, or 6. In embodiments, R¹ is selected from

wherein a1 is 0, 1, 2, or 3. In embodiments, R1 is selected from

wherein e1 is 0, 1, or 2. In embodiments, R¹ is selected fromS(═O)_(e1)R^(1B), NHC(═O)R^(1B), NR^(1B)C(═O)R^(1C),NR^(1B)C(═O)N(R^(1C))₂, NHC(═O)NR^(1B)R^(1C).

In embodiments, R¹ is 5- or 6-membered unsubstituted heteroaryl. Inembodiments, R¹ is an optionally substituted 5- or 6-membered heteroarylcomprising a substituent (e.g., 1, 2, or 3 substituents) selected from hF, Cl, Br, —CN, —NR₄R₅, —NO₂, —CF₃, —OCF₃, —OH, —C₁-C₆alkyl, or—OC₁-C₆alkyl. In embodiments, R¹ is optionally substituted bicyclicheteroaryl ring (e.g., benzothiophene, benzofuran, indole, oxindole, orbenzimidazole). In embodiments, R¹ is substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, or substituted orunsubstituted heterocycloalkyl. In embodiments, R¹ is substituted orunsubstituted alkoxy. In embodiments, R¹ is haloalkyl, or haloalkoxy.

In embodiments, R² is selected from the group consisting of substitutedor unsubstituted phenyl, substituted or unsubstituted 5- or 6-memberedheteroaryl, substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, and substituted or unsubstitutedheterocycloalkyl. In embodiments, R² is —O (substituted or unsubstitutedalkyl). In embodiments, R² is haloalkyl, or haloalkoxy.

In embodiments, R³ is independently hydrogen, F, Cl, Br, —CN, —CF₃,—OCF₃, or —OH. In embodiments, R³ is substituted or unsubstituted C₁-C₆alkyl, —O-substituted or unsubstituted C₁-C₆ alkyl), —C(═O)(substitutedor unsubstituted C₁-C₆ alkyl), or CO₂H. In embodiments, R³ issubstituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. In embodiments, R³ is —NR¹³R¹⁴,—OR¹⁶, —C(O)NR¹³R¹⁴, or —C(O)—OR¹⁵.

In embodiments, R⁴ is independently hydrogen, F, Cl, Br, —CN, —CF₃,—OCF₃, or —OH. In embodiments, R⁴ is substituted or unsubstituted C₁-C₆alkyl, —O-substituted or unsubstituted C₁-C₆ alkyl), —C(═O)(substitutedor unsubstituted C₁-C₆ alkyl), or CO₂H. In embodiments, R⁴ issubstituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. In embodiments, R⁴ is —NR¹⁷R¹⁸,—OR²⁰, —C(O)NR¹⁷R¹⁸, or —C(O)—OR¹⁹.

In embodiments, R⁵ is independently hydrogen, F, Cl, Br, —CN, —CF₃,—OCF₃, or —OH. In embodiments, R⁵ is substituted or unsubstituted C₁-C₆alkyl, —O-substituted or unsubstituted C₁-C₆ alkyl), —C(═O)(substitutedor unsubstituted C₁-C₆ alkyl), or CO₂H. In embodiments, R⁵ issubstituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. In embodiments, R⁵ is —NR²¹R²²,—OR²⁴, —C(O)NR²¹R²², or —C(O)—OR²³.

In embodiments, R⁶ is independently hydrogen, F, Cl, Br, —CN, —CF₃,—OCF₃, or —OH. In embodiments, R⁶ is substituted or unsubstituted C₁-C₆alkyl, —O-substituted or unsubstituted C₁-C₆ alkyl), —C(═O)(substitutedor unsubstituted C₁-C₆ alkyl), or CO₂H. In embodiments, R⁶ issubstituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. In embodiments, R⁶ is —NR²⁵R²⁶,—OR²⁸, —C(O)NR²⁵R²⁶, or —C(O)—OR²⁷.

In embodiments, the compound has a structure according to the formula,

-   -   or a pharmaceutically acceptable salt thereof.    -   Z is independently a covalent bond, —O—, —NR⁹—, —NR⁹C(O)—,        —C(O)NR⁹—, —O—C(O)—, or —C(O)—O—.    -   L¹ is independently a bond, substituted or unsubstituted        alkylene, substituted or unsubstituted heteroalkylene,        substituted or unsubstituted cycloalkylene, substituted or        unsubstituted heterocycloalkylene, substituted or unsubstituted        arylene, or substituted or unsubstituted heteroarylene.    -   R¹ is independently hydrogen, —NR¹⁰R¹¹, —OR¹², substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl.    -   R² is independently hydrogen, substituted or unsubstituted        alkyl, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl.    -   R³ is independently hydrogen, halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³,        —OCX³ ₃, —OCHX³ ₂, —OCH₂X³, —CN, —SO_(n3)R¹⁶, —SO_(v3)NR¹³R¹⁴,        —NHC(O)NR¹³R¹⁴, —N(O)_(m3), —NR¹³R¹⁴, —C(O)R¹⁵, —C(O)—OR¹⁵,        —C(O)NR¹³R¹⁴, —OR¹⁶, —NR¹³SO₂R¹⁶, —NR¹³C(O)R¹⁵, —NR¹³C(O)OR¹⁵,        —NR¹³OR¹⁵, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl.    -   R⁴ is independently hydrogen, halogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴,        —OCX⁴ ₃, —OCHX⁴ ₂, —OCH₂X⁴, —CN, —SO_(n4)R²⁰, —SO_(v4)NR¹⁷R¹⁸,        —NHC(O)NR¹⁷R¹⁸, —N(O)_(m4), —NR¹⁷R¹⁸, —C(O)R¹⁹, —C(O)—OR¹⁹,        —C(O)NR¹⁷R¹⁸, —OR²⁰, —NR¹⁷SO₂R²⁰, —NR¹⁷C(O)R¹⁹, —NR¹⁷C(O)OR¹⁹,        —NR¹⁷OR¹⁹, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl.    -   R⁵ is independently hydrogen, halogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵,        —OCX⁵ ₃, —OCHX⁵ ₂, —OCH₂X⁵, —CN, —SO_(n5)R²⁴, —SO_(v5)NR²¹R²²,        —NHC(O)NR²¹R²², —N(O)_(m5), —NR²¹R²², —C(O)R²³, —C(O)—OR²³,        —C(O)NR²¹R²², —OR²⁴, —NR²¹SO₂R²⁴, —NR²¹C(O)R²³, —NR²¹C(O)OR²³,        —NR²¹OR²³, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl.    -   R⁶ is independently hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶,        —OCX⁶ ₃, —OCHX⁶ ₂, —OCH₂X⁶, —CN, —SO_(n6)R²⁸, —SO_(v6)NR²⁵R²⁶,        —NHC(O)NR²⁵R²⁶, —N(O)_(m6), —NR²⁵R²⁶, —C(O)R²⁷, —C(O)—OR²⁷,        —C(O)NR²⁵R²⁶, —OR²⁸, —NR²⁵SO₂R²⁸, —NR²⁵C(O)R²⁷, —NR²⁵C(O)OR²⁷,        —NR²⁵OR²⁷, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl.    -   Each R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸,        R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, and R²⁸ is        independently hydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X,        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;        R⁶ and R⁷, R¹⁰ and R¹¹, R¹⁴ and R¹⁵, and R¹⁸ and R¹⁹        substituents bonded to the same nitrogen atom may optionally be        joined to form a substituted or unsubstituted heterocycloalkyl        or substituted or unsubstituted heteroaryl.    -   Each X³, X⁴, X⁵, and X⁶ is independently —F, —Cl, —Br, or —I.    -   Each m3, m4, m5, and m6 is independently 1 or 2.    -   Each n3, n4, n5, and n6 is independently an integer from 0 to 3.    -   Each v3, v4, v5, and v6 is independently 1 or 2.

In embodiments, when R³-R⁶ are each H, and —Z-L¹-R² is

(—NH(CH₂)₂N(CH₂)₅) or

(—N(CH₂)₅), then R¹ is not unsubstituted phenyl. In embodiments, when Xis N, Y is CH, R³-R⁶ are each H, and R² is unsubstituted piperidine,then R¹ is not unsubstituted phenyl. In embodiments, when X is N, Y isCH, R³-R⁶ are each H, and R² is unsubstituted piperidine, then R¹ is notunsubstituted phenyl. In embodiments, when X is N, Y is CH, R³-R⁶ areeach H, R² is unsubstituted piperidine, and R¹ is aryl (e.g., phenyl),then R₁ comprises an amide substituent (e.g., —C(O)NR^(1C)R^(1D) asdescribed herein).

In embodiments, Z is independently a covalent bond or —NR⁹—; L¹ isindependently a bond, substituted or unsubstituted alkylene, substitutedor unsubstituted heteroalkylene, substituted or unsubstituted arylene,or substituted or unsubstituted heteroarylene; and R² is independentlysubstituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

In embodiments, Z is independently —NR⁹—; L¹ is independentlysubstituted or unsubstituted alkylene or substituted or unsubstitutedarylene; and R² is independently substituted or unsubstituted alkyl orsubstituted or unsubstituted heterocycloalkyl.

In embodiments, Z is independently —NH—; L¹ is independently substitutedor unsubstituted C₃-C₆ alkylene; and R² is substituted or unsubstitutedheterocycloalkyl.

In embodiments, Z is independently —NH—; L¹ is independently substitutedor unsubstituted arylene; R² is independently C₁-C₃ alkyl comprising asubstituent group R^(2A); R^(2A) is independently —NR^(2B)R^(2C),substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; and each of R^(2B) and R^(2C) is independentlyhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl, orwherein R^(2B) and R^(2C) combine to form a substituted or unsubstitutedheterocycloalkyl.

In embodiments, R¹ is substituted or unsubstituted aryl or substitutedor unsubstituted heteroaryl.

In embodiments, R¹ is aryl or heteroaryl comprising a substituent groupR^(1A); R^(1A) is independently halogen, —CN, —OR^(1B), —SR^(1B),—NR^(1C)R^(1D), —NR^(1C)C(O)R^(1B), —C(O)NR^(1C)R^(1D), —CO₂R^(1B),substituted or unsubstituted alkyl, or substituted or unsubstitutedheteroalkyl; each of R^(1B) and R^(1C) is independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(1D) is independentlysubstituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; or wherein R^(1C) and R^(1D)attached to the same nitrogen atom optionally combine to form asubstituted or unsubstituted heterocycloalkyl.

In embodiments, R¹ is phenyl comprising a substituent group—C(O)NR^(1C)R^(1D).

In embodiments, the compound has a structure according to the formula,

-   -   or a pharmaceutically acceptable salt thereof.    -   R¹ is substituted or unsubstituted heteroaryl or phenyl        comprising a substituent group R^(1A).    -   R² is substituted or unsubstituted cycloalkyl or substituted or        unsubstituted heterocycloalkyl.    -   R^(1A) is independently halogen, —CN, —OR^(1B), —SR^(1B),        —NR^(1C)R^(1D), —NR^(1C)C(O)R^(1B), —C(O)NR^(1C)R^(1D),        —CO₂R^(1B), substituted or unsubstituted alkyl, or substituted        or unsubstituted heteroalkyl.    -   Each of R^(1B) and R^(1C) is independently hydrogen, substituted        or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl.    -   R^(1D) is independently substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl; or wherein R^(1C) and        R^(1D) attached to the same nitrogen atom optionally combine to        form a substituted or unsubstituted heterocycloalkyl.

In embodiments, the compound has a structure according to the formula,

-   -   or a pharmaceutically acceptable salt thereof.    -   R¹ is substituted or unsubstituted heteroaryl or phenyl        comprising a substituent group R^(1A).    -   L¹ is independently substituted or unsubstituted arylene.    -   R^(1A) is independently halogen, —CN, —OR^(1B), —SR^(1B),        —NR^(1C)R^(1D), —NR^(1C)C(O)R^(1B), —C(O)NR^(1C)R^(1D),        —CO₂R^(1B), substituted or unsubstituted alkyl, or substituted        or unsubstituted heteroalkyl.    -   Each of R^(1B) and R^(1C) is independently hydrogen, substituted        or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl.    -   R^(1D) is independently substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl; or wherein R^(1C) and        R^(1D) attached to the same nitrogen atom optionally combine to        form a substituted or unsubstituted heterocycloalkyl.    -   R^(2A) is independently —NR^(2B)R^(2C), substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl.    -   Each of R^(2B) and R^(2C) is independently hydrogen, substituted        or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl,        or wherein R^(2B) and R^(2C) combine to form a substituted or        unsubstituted heterocycloalkyl.

In embodiments, R¹ is phenyl comprising a substituent group R^(1A); andR^(1A) is —C(O)NR^(1C)R^(1D).

In embodiments, R^(1A) is para to the carbon attached to the quinolinemoiety.

In embodiments, the compound has a structure according to the formula,

-   -   or a pharmaceutically acceptable salt thereof.    -   R^(1C) is independently hydrogen, substituted or unsubstituted        alkyl, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl.    -   R^(1D) is independently substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl; or wherein R^(1C) and        R^(1D) attached to the same nitrogen atom optionally combine to        form a substituted or unsubstituted heterocycloalkyl.

In embodiments, Z is independently —NR⁹—; and L¹ is independentlysubstituted or unsubstituted alkylene or substituted or unsubstitutedarylene.

In embodiments, each of R³, R⁴, R⁵, R⁶, and R⁸ is hydrogen.

In embodiments, the compound has a structure according to the formula,

-   -   or a pharmaceutically acceptable salt thereof.    -   X is independently N or CR⁷.    -   Y is independently N or CR⁸.    -   Z is independently a covalent bond, —O—, —NR⁹—, —NR⁹C(O)—,        —C(O)NR⁹—, —O—C(O)—, or —C(O)—O—.    -   L¹ is a bond, and R² is unsubstituted alkyl or substituted or        unsubstituted heterocycloalkyl; or L¹ is substituted or        unsubstituted C₂-C₆ alkylene, and R² is or substituted or        unsubstituted heterocycloalkyl, where said heterocycloalkyl is        not unsubstituted morpholine.    -   R¹ is independently hydrogen, —NR¹⁰R¹¹, —OR¹², substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl.    -   R³ is independently hydrogen, halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³,        —OCX³ ₃, —OCHX³ ₂, —OCH₂X³, —CN, —SO_(n3)R¹⁶, —SO_(v3)NR¹³R¹⁴,        —NHC(O)NR¹³R¹⁴, —N(O)_(m3), —NR¹³R¹⁴, —C(O)R¹⁵, —C(O)—OR¹⁵,        —C(O)NR¹³R¹⁴, —OR¹⁶, —NR¹³SO₂R¹⁶, —NR¹³C(O)R¹⁵, —NR¹³C(O)OR¹⁵,        —NR¹³OR¹⁵, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl.    -   R⁴ is independently hydrogen, halogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴,        —OCX⁴ ₃, —OCHX⁴ ₂, —OCH₂X⁴, —CN, —SO_(n4)R²⁰, —SO_(v4)NR¹⁷R¹⁸,        —NHC(O)NR¹⁷R¹⁸, —N(O)_(m4), —NR¹⁷R¹⁸, —C(O)R¹⁹, —C(O)—OR¹⁹,        —C(O)NR¹⁷R¹⁸, —OR²⁰, —NR¹⁷SO₂R²⁰, —NR¹⁷C(O)R¹⁹, —NR¹⁷C(O)OR¹⁹,        —NR¹⁷OR¹⁹, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl.    -   R⁵ is independently hydrogen, halogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵,        —OCX⁵ ₃, —OCHX⁵ ₂, —OCH₂X⁵, —CN, —SO_(n5)R²⁴, —SO_(v5)NR²¹R²²,        —NHC(O)NR²¹R²², —N(O)_(m5), —NR²¹R²², —C(O)R²³, —C(O)—OR²³,        —C(O)NR²¹R²², —OR²⁴, —NR²¹SO₂R²⁴, —NR²¹C(O)R²³, —NR²¹C(O)OR²³,        —NR²¹OR²³, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl.    -   R⁶ is independently hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶,        —OCX⁶ ₃, —OCHX⁶ ₂, —OCH₂X⁶, —CN, —SO_(n6)R²⁸, —SO_(v6)NR²⁵R²⁶,        —NHC(O)NR²⁵R²⁶, —N(O)_(m6), —NR²⁵R²⁶, —C(O)R²⁷, —C(O)—OR²⁷,        —C(O)NR²⁵R²⁶, —OR²⁸, —NR²⁵SO₂R²⁸, —NR²⁵C(O)R²⁷, —NR²⁵C(O)OR²⁷,        —NR²⁵OR²⁷, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl.    -   Each R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸,        R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, and R²⁸ is        independently hydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X,        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;        R⁶ and R⁷, R¹⁰ and R¹¹, R¹⁴ and R¹⁵, and R¹⁸ and R¹⁹        substituents bonded to the same nitrogen atom may optionally be        joined to form a substituted or unsubstituted heterocycloalkyl        or substituted or unsubstituted heteroaryl.    -   Each X³, X⁴, X⁵, and X⁶ is independently —F, —Cl, —Br, or —I.    -   Each m3, m4, m5, and m6 is independently 1 or 2.    -   Each n3, n4, n5, and n6 is independently an integer from 0 to 3.    -   Each v3, v4, v5, and v6 is independently 1 or 2.

In embodiments, each of R³, R⁴, R⁵, R⁶, and R⁸ is hydrogen.

In embodiments, Z is independently a covalent bond. In embodiments, Z isindependently —O—. In embodiments, Z is independently —NR⁹—. Inembodiments, Z is independently —NR⁹C(O)—. In embodiments, Z isindependently —C(O)NR⁹—. In embodiments, Z is independently —O—C(O)—. Inembodiments, Z is independently —C(O)—O—.

In embodiments, L¹ is independently a bond. In embodiments, L¹ isindependently substituted or unsubstituted alkylene. In embodiments, L¹is independently substituted or unsubstituted heteroalkylene. Inembodiments, L¹ is independently substituted or unsubstitutedcycloalkylene. In embodiments, L¹ is independently substituted orunsubstituted heterocycloalkylene. In embodiments, L¹ is independentlysubstituted or unsubstituted arylene. In embodiments, L¹ isindependently substituted or unsubstituted heteroarylene. Inembodiments, L¹ is independently substituted alkylene. In embodiments,L¹ is independently substituted heteroalkylene. In embodiments, L¹ isindependently substituted cycloalkylene. In embodiments, L¹ isindependently substituted heterocycloalkylene. In embodiments, L¹ isindependently substituted arylene. In embodiments, L¹ is independentlysubstituted heteroarylene. In embodiments, L¹ is independentlyunsubstituted alkylene. In embodiments, L¹ is independentlyunsubstituted heteroalkylene. In embodiments, L¹ is independentlyunsubstituted cycloalkylene. In embodiments, L¹ is independentlyunsubstituted heterocycloalkylene. In embodiments, L¹ is independentlyunsubstituted arylene. In embodiments, L¹ is independently unsubstitutedheteroarylene. In embodiments, L¹ is independently substituted orunsubstituted C₁-C₆ alkylene. In embodiments, L¹ is independentlysubstituted or unsubstituted 2 to 6 membered heteroalkylene. Inembodiments, L¹ is independently substituted or unsubstituted C₃-C₈cycloalkylene. In embodiments, L¹ is independently substituted orunsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, L¹ isindependently substituted or unsubstituted C₆ arylene. In embodiments,L¹ is independently substituted or unsubstituted 5 to 6 memberedheteroarylene. In embodiments, L is independently substituted C₁-C₆alkylene. In embodiments, L¹ is independently substituted 2 to 6membered heteroalkylene. In embodiments, L¹ is independently substitutedC₃-C₈ cycloalkylene. In embodiments, L¹ is independently substituted 3to 8 membered heterocycloalkylene. In embodiments, L¹ is independentlysubstituted C₆ arylene. In embodiments, L¹ is independently substituted5 to 6 membered heteroarylene. In embodiments, L¹ is independentlyunsubstituted C₁-C₆ alkylene. In embodiments, L¹ is independentlyunsubstituted 2 to 6 membered heteroalkylene. In embodiments, L¹ isindependently unsubstituted C₃-C₈ cycloalkylene. In embodiments, L¹ isindependently unsubstituted 3 to 8 membered heterocycloalkylene. Inembodiments, L¹ is independently unsubstituted C₆ arylene. Inembodiments, L¹ is independently unsubstituted 5 to 6 memberedheteroarylene.

In embodiments, R¹ is independently hydrogen. In embodiments, R¹ isindependently —NR¹⁰R¹¹. In embodiments, R¹ is independently —OR¹². Inembodiments, R¹ is independently substituted or unsubstituted alkyl. Inembodiments, R¹ is independently substituted or unsubstitutedheteroalkyl. In embodiments, R¹ is independently substituted orunsubstituted cycloalkyl. In embodiments, R¹ is independentlysubstituted or unsubstituted heterocycloalkyl. In embodiments, R¹ isindependently substituted or unsubstituted aryl. In embodiments, R¹ isindependently or substituted or unsubstituted heteroaryl. Inembodiments, R¹ is independently substituted alkyl. In embodiments, R¹is independently substituted heteroalkyl. In embodiments, R¹ isindependently substituted cycloalkyl. In embodiments, R¹ isindependently substituted heterocycloalkyl. In embodiments, R¹ isindependently substituted aryl. In embodiments, R¹ is independentlysubstituted heteroaryl. In embodiments, R¹ is independentlyunsubstituted alkyl. In embodiments, R¹ is independently unsubstitutedheteroalkyl. In embodiments, R¹ is independently unsubstitutedcycloalkyl. In embodiments, R¹ is independently unsubstitutedheterocycloalkyl. In embodiments, R¹ is independently unsubstitutedaryl. In embodiments, R¹ is independently unsubstituted heteroaryl. Inembodiments, R¹ is independently substituted or unsubstituted C₁-C₆alkyl. In embodiments, R¹ is independently substituted or unsubstituted2 to 6 membered heteroalkyl. In embodiments, R¹ is independentlysubstituted or unsubstituted C₃-C₈ cycloalkyl. In embodiments, R¹ isindependently substituted or unsubstituted 3 to 8 memberedheterocycloalkyl. In embodiments, R¹ is independently substituted orunsubstituted C₆ aryl. In embodiments, R¹ is independently substitutedor unsubstituted 5 to 6 membered heteroaryl. In embodiments, R¹ isindependently substituted C₁-C₆ alkyl. In embodiments, R¹ isindependently substituted 2 to 6 membered heteroalkyl. In embodiments,R¹ is independently substituted C₃-C₈ cycloalkyl. In embodiments, R¹ isindependently substituted 3 to 8 membered heterocycloalkyl. Inembodiments, R¹ is independently substituted C₆ aryl. In embodiments, R¹is independently substituted 5 to 6 membered heteroaryl. In embodiments,R¹ is independently unsubstituted C₁-C₆ alkyl. In embodiments, R¹ isindependently unsubstituted 2 to 6 membered heteroalkyl. In embodiments,R¹ is independently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R¹is independently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R¹ is independently unsubstituted C₆ aryl. In embodiments,R¹ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, R² is independently hydrogen. In embodiments, R² isindependently substituted or unsubstituted alkyl. In embodiments, R² isindependently substituted or unsubstituted heteroalkyl. In embodiments,R² is independently substituted or unsubstituted cycloalkyl. Inembodiments, R² is independently substituted or unsubstitutedheterocycloalkyl. In embodiments, R² is independently substituted orunsubstituted aryl. In embodiments, R² is independently substituted orunsubstituted heteroaryl. In embodiments, R² is independentlysubstituted alkyl. In embodiments, R² is independently substitutedheteroalkyl. In embodiments, R² is independently substituted cycloalkyl.In embodiments, R² is independently substituted heterocycloalkyl. Inembodiments, R² is independently substituted aryl. In embodiments, R² isindependently substituted heteroaryl. In embodiments, R² isindependently unsubstituted alkyl. In embodiments, R² is independentlyunsubstituted heteroalkyl. In embodiments, R² is independentlyunsubstituted cycloalkyl. In embodiments, R² is independentlyunsubstituted heterocycloalkyl. In embodiments, R² is independentlyunsubstituted aryl. In embodiments, R² is independently unsubstitutedheteroaryl. In embodiments, R² is independently substituted orunsubstituted C₁-C₆ alkyl. In embodiments, R² is independentlysubstituted or unsubstituted 2 to 6 membered heteroalkyl. Inembodiments, R² is independently substituted or unsubstituted C₃-C₈cycloalkyl. In embodiments, R² is independently substituted orunsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R² isindependently substituted or unsubstituted C₆ aryl. In embodiments, R²is independently substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R² is independently substituted C₁-C₆ alkyl.In embodiments, R² is independently substituted 2 to 6 memberedheteroalkyl. In embodiments, R² is independently substituted C₃-C₆cycloalkyl. In embodiments, R² is independently substituted 3 to 8membered heterocycloalkyl. In embodiments, R² is independentlysubstituted C₆ aryl. In embodiments, R² is independently substituted 5to 6 membered heteroaryl. In embodiments, R² is independentlyunsubstituted C₁-C₆ alkyl. In embodiments, R² is independentlyunsubstituted 2 to 6 membered heteroalkyl. In embodiments, R² isindependently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R² isindependently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R² is independently unsubstituted C₆ aryl. In embodiments,R² is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, R³ is independently hydrogen. In embodiments, R³ isindependently halogen. In embodiments, R³ is independently —CX³ ₃. Inembodiments, R³ is independently —CHX³ ₂. In embodiments, R³ isindependently —CH₂X³. In embodiments, R³ is independently —OCX³ ₃. Inembodiments, R³ is independently —OCHX³ ₂. In embodiments, R³ isindependently —OCH₂X³. In embodiments, R³ is independently —CN,—SO_(n3)R¹⁶. In embodiments, R³ is independently —SO_(v3)NR¹³R¹⁴. Inembodiments, R³ is independently —NHC(O)NR¹³R¹⁴. In embodiments, R³ isindependently —N(O)_(m3). In embodiments, R³ is independently —NR¹³R¹⁴,—C(O)R¹⁵. In embodiments, R³ is independently —C(O)—OR¹⁵. Inembodiments, R³ is independently —C(O)NR¹³R¹⁴. In embodiments, R³ isindependently —OR¹⁶. In embodiments, R³ is independently —NR¹³SO₂R¹⁶. Inembodiments, R³ is independently —NR¹³C(O)R¹⁵. In embodiments, R³ isindependently —NR¹³C(O)OR¹⁵. In embodiments, R³ is independently—NR¹³OR¹⁵. In embodiments, R³ is independently substituted orunsubstituted alkyl. In embodiments, R³ is independently substituted orunsubstituted heteroalkyl. In embodiments, R³ is independentlysubstituted or unsubstituted cycloalkyl. In embodiments, R³ isindependently substituted or unsubstituted heterocycloalkyl. Inembodiments, R³ is independently substituted or unsubstituted aryl. Inembodiments, R³ is independently substituted or unsubstitutedheteroaryl. In embodiments, R³ is independently substituted alkyl. Inembodiments, R³ is independently substituted heteroalkyl. Inembodiments, R³ is independently substituted cycloalkyl. In embodiments,R³ is independently substituted heterocycloalkyl. In embodiments, R³ isindependently substituted aryl. In embodiments, R³ is independentlysubstituted heteroaryl. In embodiments, R³ is independentlyunsubstituted alkyl. In embodiments, R³ is independently unsubstitutedheteroalkyl. In embodiments, R³ is independently unsubstitutedcycloalkyl. In embodiments, R³ is independently unsubstitutedheterocycloalkyl. In embodiments, R³ is independently unsubstitutedaryl. In embodiments, R³ is independently unsubstituted heteroaryl. Inembodiments, R³ is independently substituted or unsubstituted C₁-C₆alkyl. In embodiments, R³ is independently substituted or unsubstituted2 to 6 membered heteroalkyl. In embodiments, R³ is independentlysubstituted or unsubstituted C₃-C₈ cycloalkyl. In embodiments, R³ isindependently substituted or unsubstituted 3 to 8 memberedheterocycloalkyl. In embodiments, R³ is independently substituted orunsubstituted C₆ aryl. In embodiments, R³ is independently substitutedor unsubstituted 5 to 6 membered heteroaryl. In embodiments, R³ isindependently substituted C₁-C₆ alkyl. In embodiments, R³ isindependently substituted 2 to 6 membered heteroalkyl. In embodiments,R³ is independently substituted C₃-C₈ cycloalkyl. In embodiments, R³ isindependently substituted 3 to 8 membered heterocycloalkyl. Inembodiments, R³ is independently substituted C₆ aryl. In embodiments, R³is independently substituted 5 to 6 membered heteroaryl. In embodiments,R³ is independently unsubstituted C₁-C₆ alkyl. In embodiments, R³ isindependently unsubstituted 2 to 6 membered heteroalkyl. In embodiments,R³ is independently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R³is independently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R³ is independently unsubstituted C₆ aryl. In embodiments,R³ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, R⁴ is independently hydrogen. In embodiments, R⁴ isindependently halogen. In embodiments, R⁴ is independently —CX⁴ ₃. Inembodiments, R⁴ is independently —CHX⁴ ₂. In embodiments, R⁴ isindependently —CH₂X⁴. In embodiments, R⁴ is independently —OCX⁴ ₃. Inembodiments, R⁴ is independently —OCHX⁴ ₂. In embodiments, R⁴ isindependently —OCH₂X⁴. In embodiments, R⁴ is independently —CN. Inembodiments, R⁴ is independently —SO_(n4)R²⁰. In embodiments, R⁴ isindependently —SO_(v4)NR¹⁷R¹⁸. In embodiments, R⁴ is independently—NHC(O)NR¹⁷R¹⁸. In embodiments, R⁴ is independently —N(O)_(m4). Inembodiments, R⁴ is independently —NR¹⁷R¹⁸. In embodiments, R⁴ isindependently —C(O)R¹⁹. In embodiments, R⁴ is independently —C(O)—OR¹⁹.In embodiments, R⁴ is independently —C(O)NR¹⁷R¹⁸. In embodiments, R⁴ isindependently —OR²⁰. In embodiments, R⁴ is independently —NR¹⁷SO₂R²⁰. Inembodiments, R⁴ is independently —NR¹⁷C(O)R¹⁹. In embodiments, R⁴ isindependently —NR¹⁷C(O)OR¹⁹. In embodiments, R⁴ is independently—NR¹⁷OR¹⁹. In embodiments, R⁴ is independently substituted orunsubstituted alkyl. In embodiments, R⁴ is independently substituted orunsubstituted heteroalkyl. In embodiments, R⁴ is independentlysubstituted or unsubstituted cycloalkyl. In embodiments, R⁴ isindependently substituted or unsubstituted heterocycloalkyl. Inembodiments, R⁴ is independently substituted or unsubstituted aryl. Inembodiments, R⁴ is independently or substituted or unsubstitutedheteroaryl. In embodiments, R⁴ is independently substituted alkyl. Inembodiments, R⁴ is independently substituted heteroalkyl. Inembodiments, R⁴ is independently substituted cycloalkyl. In embodiments,R⁴ is independently substituted heterocycloalkyl. In embodiments, R⁴ isindependently substituted aryl. In embodiments, R⁴ is independentlysubstituted heteroaryl. In embodiments, R⁴ is independentlyunsubstituted alkyl. In embodiments, R⁴ is independently unsubstitutedheteroalkyl. In embodiments, R⁴ is independently unsubstitutedcycloalkyl. In embodiments, R⁴ is independently unsubstitutedheterocycloalkyl. In embodiments, R⁴ is independently unsubstitutedaryl. In embodiments, R⁴ is independently unsubstituted heteroaryl. Inembodiments, R⁴ is independently substituted or unsubstituted C₁-C₆alkyl. In embodiments, R⁴ is independently substituted or unsubstituted2 to 6 membered heteroalkyl. In embodiments, R⁴ is independentlysubstituted or unsubstituted C₃-C₈ cycloalkyl. In embodiments, R⁴ isindependently substituted or unsubstituted 3 to 8 memberedheterocycloalkyl. In embodiments, R⁴ is independently substituted orunsubstituted C₆ aryl. In embodiments, R⁴ is independently substitutedor unsubstituted 5 to 6 membered heteroaryl. In embodiments, R⁴ isindependently substituted C₁-C₆ alkyl. In embodiments, R⁴ isindependently substituted 2 to 6 membered heteroalkyl. In embodiments,R⁴ is independently substituted C₃-C₈ cycloalkyl. In embodiments, R⁴ isindependently substituted 3 to 8 membered heterocycloalkyl. Inembodiments, R⁴ is independently substituted C₆ aryl. In embodiments, R⁴is independently substituted 5 to 6 membered heteroaryl. In embodiments,R⁴ is independently unsubstituted C₁-C₆ alkyl. In embodiments, R⁴ isindependently unsubstituted 2 to 6 membered heteroalkyl. In embodiments,R⁴ is independently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R⁴is independently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R⁴ is independently unsubstituted C₆ aryl. In embodiments,R⁴ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, R⁵ is independently hydrogen. In embodiments, R⁵ isindependently halogen. In embodiments, R⁵ is independently —CX⁵ ₃. Inembodiments, R⁵ is independently —CHX⁵ ₂. In embodiments, R⁵ isindependently —CH₂X⁵. In embodiments, R⁵ is independently —OCX⁵ ₃. Inembodiments, R⁵ is independently —OCHX⁵ ₂. In embodiments, R⁵ isindependently —OCH₂X⁵. In embodiments, R⁵ is independently —CN. Inembodiments, R⁵ is independently —SO_(n5)R²⁴. In embodiments, R⁵ isindependently —SO_(v5)NR²¹R²². In embodiments, R⁵ is independently—NHC(O)NR²¹R²². In embodiments, R⁵ is independently —N(O)_(m5). Inembodiments, R⁵ is independently —NR²¹R²². In embodiments, R⁵ isindependently —C(O)R²³. In embodiments, R⁵ is independently —C(O)—OR²³.In embodiments, R⁵ is independently —C(O)NR²¹R²². In embodiments, R⁵ isindependently —OR²⁴. In embodiments, R⁵ is independently —NR²¹SO₂R²⁴. Inembodiments, R⁵ is independently —NR²¹C(O)R²³. In embodiments, R⁵ isindependently —NR²¹C(O)OR²³. In embodiments, R⁵ is independently—NR²¹OR²³. In embodiments, R⁵ is independently substituted orunsubstituted alkyl. In embodiments, R⁵ is independently substituted orunsubstituted heteroalkyl. In embodiments, R⁵ is independentlysubstituted or unsubstituted cycloalkyl. In embodiments, R⁵ isindependently substituted or unsubstituted heterocycloalkyl. Inembodiments, R⁵ is independently substituted or unsubstituted aryl. Inembodiments, R⁵ is independently or substituted or unsubstitutedheteroaryl. In embodiments, R⁵ is independently substituted alkyl. Inembodiments, R⁵ is independently substituted heteroalkyl. Inembodiments, R⁵ is independently substituted cycloalkyl. In embodiments,R⁵ is independently substituted heterocycloalkyl. In embodiments, R⁵ isindependently substituted aryl. In embodiments, R⁵ is independentlysubstituted heteroaryl. In embodiments, R⁵ is independentlyunsubstituted alkyl. In embodiments, R⁵ is independently unsubstitutedheteroalkyl. In embodiments, R⁵ is independently unsubstitutedcycloalkyl. In embodiments, R⁵ is independently unsubstitutedheterocycloalkyl. In embodiments, R⁵ is independently unsubstitutedaryl. In embodiments, R⁵ is independently unsubstituted heteroaryl. Inembodiments, R⁵ is independently substituted or unsubstituted C₁-C₆alkyl. In embodiments, R⁵ is independently substituted or unsubstituted2 to 6 membered heteroalkyl. In embodiments, R⁵ is independentlysubstituted or unsubstituted C₃-C₈ cycloalkyl. In embodiments, R⁵ isindependently substituted or unsubstituted 3 to 8 memberedheterocycloalkyl. In embodiments, R⁵ is independently substituted orunsubstituted C₆ aryl. In embodiments, R⁵ is independently substitutedor unsubstituted 5 to 6 membered heteroaryl. In embodiments, R⁵ isindependently substituted C₁-C₆ alkyl. In embodiments, R⁵ isindependently substituted 2 to 6 membered heteroalkyl. In embodiments,R⁵ is independently substituted C₃-C₈ cycloalkyl. In embodiments, R⁵ isindependently substituted 3 to 8 membered heterocycloalkyl. Inembodiments, R⁵ is independently substituted C₆ aryl. In embodiments, R⁵is independently substituted 5 to 6 membered heteroaryl. In embodiments,R⁵ is independently unsubstituted C₁-C₆ alkyl. In embodiments, R⁵ isindependently unsubstituted 2 to 6 membered heteroalkyl. In embodiments,R⁵ is independently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R⁵is independently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R⁵ is independently unsubstituted C₆ aryl. In embodiments,R⁵ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, R⁶ is independently hydrogen. In embodiments, R⁶ isindependently halogen. In embodiments, R⁶ is independently —CX⁶ ₃. Inembodiments, R⁶ is independently —CHX⁶ ₂. In embodiments, R⁶ isindependently —CH₂X⁶. In embodiments, R⁶ is independently —OCX⁶ ₃. Inembodiments, R⁶ is independently —OCHX⁶ ₂. In embodiments, R⁶ isindependently —OCH₂X⁶. In embodiments, R⁶ is independently —CN. Inembodiments, R⁶ is independently —SO_(n6)R²⁸. In embodiments, R⁶ isindependently —SO_(v6)NR²⁵R²⁶. In embodiments, R⁶ is independently—NHC(O)NR²⁵R²⁶. In embodiments, R⁶ is independently —N(O)_(m6). Inembodiments, R⁶ is independently —NR²⁵R²⁶. In embodiments, R⁶ isindependently —C(O)R²⁷. In embodiments, R⁶ is independently —C(O)—OR²⁷.In embodiments, R⁶ is independently —C(O)NR²⁵R²⁶. In embodiments, R⁶ isindependently —OR²⁸. In embodiments, R⁶ is independently —NR²⁵SO₂R²⁸. Inembodiments, R⁶ is independently —NR²⁵C(O)R²⁷. In embodiments, R⁶ isindependently —NR²⁵C(O)OR²⁷. In embodiments, R⁶ is independently—NR²⁵OR²⁷. In embodiments, R⁶ is independently substituted orunsubstituted alkyl. In embodiments, R⁶ is independently substituted orunsubstituted heteroalkyl. In embodiments, R⁶ is independentlysubstituted or unsubstituted cycloalkyl. In embodiments, R⁶ isindependently substituted or unsubstituted heterocycloalkyl. Inembodiments, R⁶ is independently substituted or unsubstituted aryl. Inembodiments, R⁶ is independently or substituted or unsubstitutedheteroaryl. In embodiments, R⁶ is independently substituted alkyl. Inembodiments, R⁶ is independently substituted heteroalkyl. Inembodiments, R⁶ is independently substituted cycloalkyl. In embodiments,R⁶ is independently substituted heterocycloalkyl. In embodiments, R⁶ isindependently substituted aryl. In embodiments, R⁶ is independentlysubstituted heteroaryl. In embodiments, R⁶ is independentlyunsubstituted alkyl. In embodiments, R⁶ is independently unsubstitutedheteroalkyl. In embodiments, R⁶ is independently unsubstitutedcycloalkyl. In embodiments, R⁶ is independently unsubstitutedheterocycloalkyl. In embodiments, R⁶ is independently unsubstitutedaryl. In embodiments, R⁶ is independently unsubstituted heteroaryl. Inembodiments, R⁶ is independently substituted or unsubstituted C₁-C₆alkyl. In embodiments, R⁶ is independently substituted or unsubstituted2 to 6 membered heteroalkyl. In embodiments, R⁶ is independentlysubstituted or unsubstituted C₃-C₈ cycloalkyl. In embodiments, R⁶ isindependently substituted or unsubstituted 3 to 8 memberedheterocycloalkyl. In embodiments, R⁶ is independently substituted orunsubstituted C₆ aryl. In embodiments, R⁶ is independently substitutedor unsubstituted 5 to 6 membered heteroaryl. In embodiments, R⁶ isindependently substituted C₁-C₆ alkyl. In embodiments, R⁶ isindependently substituted 2 to 6 membered heteroalkyl. In embodiments,R⁶ is independently substituted C₃-C₈ cycloalkyl. In embodiments, R⁶ isindependently substituted 3 to 8 membered heterocycloalkyl. Inembodiments, R⁶ is independently substituted C₆ aryl. In embodiments, R⁶is independently substituted 5 to 6 membered heteroaryl. In embodiments,R⁶ is independently unsubstituted C₁-C₆ alkyl. In embodiments, R⁶ isindependently unsubstituted 2 to 6 membered heteroalkyl. In embodiments,R⁶ is independently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R⁶is independently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R⁶ is independently unsubstituted C₆ aryl. In embodiments,R⁶ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, each R⁷ is independently hydrogen. In embodiments, eachR⁷ is independently —CX₃. In embodiments, each R⁷ is independently —CN.In embodiments, each R⁷ is independently —COOH. In embodiments, each R⁷is independently —CONH₂. In embodiments, each R⁷ is independently —CHX₂.In embodiments, each R⁷ is independently —CH₂X. In embodiments, each R⁷is independently substituted or unsubstituted alkyl. In embodiments,each R⁷ is independently substituted or unsubstituted heteroalkyl. Inembodiments, each R⁷ is independently substituted or unsubstitutedcycloalkyl. In embodiments, each R⁷ is independently substituted orunsubstituted heterocycloalkyl. In embodiments, each R⁷ is independentlysubstituted or unsubstituted aryl. In embodiments, each R⁷ isindependently or substituted or unsubstituted heteroaryl. Inembodiments, R⁷ is independently substituted alkyl. In embodiments, R⁷is independently substituted heteroalkyl. In embodiments, R⁷ isindependently substituted cycloalkyl. In embodiments, R⁷ isindependently substituted heterocycloalkyl. In embodiments, R⁷ isindependently substituted aryl. In embodiments, R⁷ is independentlysubstituted heteroaryl. In embodiments, R⁷ is independentlyunsubstituted alkyl. In embodiments, R⁷ is independently unsubstitutedheteroalkyl. In embodiments, R⁷ is independently unsubstitutedcycloalkyl. In embodiments, R⁷ is independently unsubstitutedheterocycloalkyl. In embodiments, R⁷ is independently unsubstitutedaryl. In embodiments, R⁷ is independently unsubstituted heteroaryl. Inembodiments, R⁷ is independently substituted or unsubstituted C₁-C₆alkyl. In embodiments, R⁷ is independently substituted or unsubstituted2 to 6 membered heteroalkyl. In embodiments, R⁷ is independentlysubstituted or unsubstituted C₃-C₈ cycloalkyl. In embodiments, R⁷ isindependently substituted or unsubstituted 3 to 8 memberedheterocycloalkyl. In embodiments, R⁷ is independently substituted orunsubstituted C₆ aryl. In embodiments, R⁷ is independently substitutedor unsubstituted 5 to 6 membered heteroaryl. In embodiments, R⁷ isindependently substituted C₁-C₆ alkyl. In embodiments, R⁷ isindependently substituted 2 to 6 membered heteroalkyl. In embodiments,R⁷ is independently substituted C₃-C₈ cycloalkyl. In embodiments, R⁷ isindependently substituted 3 to 8 membered heterocycloalkyl. Inembodiments, R⁷ is independently substituted C₆ aryl. In embodiments, R⁷is independently substituted 5 to 6 membered heteroaryl. In embodiments,R⁷ is independently unsubstituted C₁-C₆ alkyl. In embodiments, R⁷ isindependently unsubstituted 2 to 6 membered heteroalkyl. In embodiments,R⁷ is independently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R⁷is independently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R⁷ is independently unsubstituted C₆ aryl. In embodiments,R⁷ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, each R⁸ is independently hydrogen. In embodiments, eachR⁸ is independently —CX₃. In embodiments, each R⁸ is independently —CN.In embodiments, each R⁸ is independently —COOH. In embodiments, each R⁸is independently —CONH₂. In embodiments, each R⁸ is independently —CHX₂.In embodiments, each R⁸ is independently —CH₂X. In embodiments, each R⁸is independently substituted or unsubstituted alkyl. In embodiments,each R⁸ is independently substituted or unsubstituted heteroalkyl. Inembodiments, each R⁸ is independently substituted or unsubstitutedcycloalkyl. In embodiments, each R⁸ is independently substituted orunsubstituted heterocycloalkyl. In embodiments, each R⁸ is independentlysubstituted or unsubstituted aryl. In embodiments, each R⁸ isindependently or substituted or unsubstituted heteroaryl. Inembodiments, R⁸ is independently substituted alkyl. In embodiments, R⁸is independently substituted heteroalkyl. In embodiments, R⁸ isindependently substituted cycloalkyl. In embodiments, R⁸ isindependently substituted heterocycloalkyl. In embodiments, R⁸ isindependently substituted aryl. In embodiments, R⁸ is independentlysubstituted heteroaryl. In embodiments, R⁸ is independentlyunsubstituted alkyl. In embodiments, R⁸ is independently unsubstitutedheteroalkyl. In embodiments, R⁸ is independently unsubstitutedcycloalkyl. In embodiments, R⁸ is independently unsubstitutedheterocycloalkyl. In embodiments, R⁸ is independently unsubstitutedaryl. In embodiments, R⁸ is independently unsubstituted heteroaryl. Inembodiments, R⁸ is independently substituted or unsubstituted C₁-C₆alkyl. In embodiments, R⁸ is independently substituted or unsubstituted2 to 6 membered heteroalkyl. In embodiments, R⁸ is independentlysubstituted or unsubstituted C₃-C₈ cycloalkyl. In embodiments, R⁸ isindependently substituted or unsubstituted 3 to 8 memberedheterocycloalkyl. In embodiments, R⁸ is independently substituted orunsubstituted C₆ aryl. In embodiments, R⁸ is independently substitutedor unsubstituted 5 to 6 membered heteroaryl. In embodiments, R⁸ isindependently substituted C₁-C₆ alkyl. In embodiments, R⁸ isindependently substituted 2 to 6 membered heteroalkyl. In embodiments,R⁸ is independently substituted C₃-C₈ cycloalkyl. In embodiments, R⁸ isindependently substituted 3 to 8 membered heterocycloalkyl. Inembodiments, R⁸ is independently substituted C₆ aryl. In embodiments, R⁸is independently substituted 5 to 6 membered heteroaryl. In embodiments,R⁸ is independently unsubstituted C₁-C₆ alkyl. In embodiments, R⁸ isindependently unsubstituted 2 to 6 membered heteroalkyl. In embodiments,R⁸ is independently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R⁸is independently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R⁸ is independently unsubstituted C₆ aryl. In embodiments,R⁸ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, each R⁹ is independently hydrogen. In embodiments, eachR⁹ is independently —CX₃. In embodiments, each R⁹ is independently —CN.In embodiments, each R⁹ is independently —COOH. In embodiments, each R⁹is independently —CONH₂. In embodiments, each R⁹ is independently —CHX₂.In embodiments, each R⁹ is independently —CH₂X. In embodiments, each R⁹is independently substituted or unsubstituted alkyl. In embodiments,each R⁹ is independently substituted or unsubstituted heteroalkyl. Inembodiments, each R⁹ is independently substituted or unsubstitutedcycloalkyl. In embodiments, each R⁹ is independently substituted orunsubstituted heterocycloalkyl. In embodiments, each R⁹ is independentlysubstituted or unsubstituted aryl. In embodiments, each R⁹ isindependently or substituted or unsubstituted heteroaryl. Inembodiments, R⁹ is independently substituted alkyl. In embodiments, R⁹is independently substituted heteroalkyl. In embodiments, R⁹ isindependently substituted cycloalkyl. In embodiments, R⁹ isindependently substituted heterocycloalkyl. In embodiments, R⁹ isindependently substituted aryl. In embodiments, R⁹ is independentlysubstituted heteroaryl. In embodiments, R⁹ is independentlyunsubstituted alkyl. In embodiments, R⁹ is independently unsubstitutedheteroalkyl. In embodiments, R⁹ is independently unsubstitutedcycloalkyl. In embodiments, R⁹ is independently unsubstitutedheterocycloalkyl. In embodiments, R⁹ is independently unsubstitutedaryl. In embodiments, R⁹ is independently unsubstituted heteroaryl. Inembodiments, R⁹ is independently substituted or unsubstituted C₁-C₆alkyl. In embodiments, R⁹ is independently substituted or unsubstituted2 to 6 membered heteroalkyl. In embodiments, R⁹ is independentlysubstituted or unsubstituted C₃-C₈ cycloalkyl. In embodiments, R⁹ isindependently substituted or unsubstituted 3 to 8 memberedheterocycloalkyl. In embodiments, R⁹ is independently substituted orunsubstituted C₆ aryl. In embodiments, R⁹ is independently substitutedor unsubstituted 5 to 6 membered heteroaryl. In embodiments, R⁹ isindependently substituted C₁-C₆ alkyl. In embodiments, R⁹ isindependently substituted 2 to 6 membered heteroalkyl. In embodiments,R⁹ is independently substituted C₃-C₈ cycloalkyl. In embodiments, R⁹ isindependently substituted 3 to 8 membered heterocycloalkyl. Inembodiments, R⁹ is independently substituted C₆ aryl. In embodiments, R⁹is independently substituted 5 to 6 membered heteroaryl. In embodiments,R⁹ is independently unsubstituted C₁-C₆ alkyl. In embodiments, R⁹ isindependently unsubstituted 2 to 6 membered heteroalkyl. In embodiments,R⁹ is independently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R⁹is independently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R⁹ is independently unsubstituted C₆ aryl. In embodiments,R⁹ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, each R¹⁰ is independently hydrogen. In embodiments, eachR¹⁰ is independently —CX₃. In embodiments, each R¹⁰ is independently—CN. In embodiments, each R¹⁰ is independently —COOH. In embodiments,each R¹⁰ is independently —CONH₂. In embodiments, each R¹⁰ isindependently —CHX₂. In embodiments, each R¹⁰ is independently —CH₂X. Inembodiments, each R¹⁰ is independently substituted or unsubstitutedalkyl. In embodiments, each R¹⁰ is independently substituted orunsubstituted heteroalkyl. In embodiments, each R¹⁰ is independentlysubstituted or unsubstituted cycloalkyl. In embodiments, each R¹⁰ isindependently substituted or unsubstituted heterocycloalkyl. Inembodiments, each R¹⁰ is independently substituted or unsubstitutedaryl. In embodiments, each R¹⁰ is independently or substituted orunsubstituted heteroaryl. In embodiments, R¹⁰ is independentlysubstituted alkyl. In embodiments, R¹⁰ is independently substitutedheteroalkyl. In embodiments, R¹⁰ is independently substitutedcycloalkyl. In embodiments, R¹⁰ is independently substitutedheterocycloalkyl. In embodiments, R¹⁰ is independently substituted aryl.In embodiments, R¹⁰ is independently substituted heteroaryl. Inembodiments, R¹⁰ is independently unsubstituted alkyl. In embodiments,R¹⁰ is independently unsubstituted heteroalkyl. In embodiments, R¹⁰ isindependently unsubstituted cycloalkyl. In embodiments, R¹⁰ isindependently unsubstituted heterocycloalkyl. In embodiments, R¹⁰ isindependently unsubstituted aryl. In embodiments, R¹⁰ is independentlyunsubstituted heteroaryl. In embodiments, R¹⁰ is independentlysubstituted or unsubstituted C₁-C₆ alkyl. In embodiments, R¹⁰ isindependently substituted or unsubstituted 2 to 6 membered heteroalkyl.In embodiments, R¹⁰ is independently substituted or unsubstituted C₃-C₈cycloalkyl. In embodiments, R¹⁰ is independently substituted orunsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R¹⁰ isindependently substituted or unsubstituted C₆ aryl. In embodiments, R¹⁰is independently substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R¹⁰ is independently substituted C₁-C₆alkyl. In embodiments, R¹⁰ is independently substituted 2 to 6 memberedheteroalkyl. In embodiments, R¹⁰ is independently substituted C₃-C₈cycloalkyl. In embodiments, R¹⁰ is independently substituted 3 to 8membered heterocycloalkyl. In embodiments, R¹⁰ is independentlysubstituted C₆ aryl. In embodiments, R¹⁰ is independently substituted 5to 6 membered heteroaryl. In embodiments, R¹⁰ is independentlyunsubstituted C₁-C₆ alkyl. In embodiments, R⁹ is independentlyunsubstituted 2 to 6 membered heteroalkyl. In embodiments, R¹⁰ isindependently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R¹⁰ isindependently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R¹⁰ is independently unsubstituted C₆ aryl. In embodiments,R¹⁰ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, each R¹¹ is independently hydrogen. In embodiments, eachR¹¹ is independently —CX₃. In embodiments, each R¹¹ is independently—CN. In embodiments, each R¹¹ is independently —COOH. In embodiments,each R¹¹ is independently —CONH₂. In embodiments, each R¹¹ isindependently —CHX₂. In embodiments, each R¹¹ is independently —CH₂X. Inembodiments, each R¹¹ is independently substituted or unsubstitutedalkyl. In embodiments, each R¹¹ is independently substituted orunsubstituted heteroalkyl. In embodiments, each R¹¹ is independentlysubstituted or unsubstituted cycloalkyl. In embodiments, each R¹¹ isindependently substituted or unsubstituted heterocycloalkyl. Inembodiments, each R¹¹ is independently substituted or unsubstitutedaryl. In embodiments, each R¹¹ is independently or substituted orunsubstituted heteroaryl. In embodiments, R¹¹ is independentlysubstituted alkyl. In embodiments, R¹¹ is independently substitutedheteroalkyl. In embodiments, R¹¹ is independently substitutedcycloalkyl. In embodiments, R¹¹ is independently substitutedheterocycloalkyl. In embodiments, R¹¹ is independently substituted aryl.In embodiments, R¹¹ is independently substituted heteroaryl. Inembodiments, R¹¹ is independently unsubstituted alkyl. In embodiments,R¹¹ is independently unsubstituted heteroalkyl. In embodiments, R¹¹ isindependently unsubstituted cycloalkyl. In embodiments, R¹¹ isindependently unsubstituted heterocycloalkyl. In embodiments, R¹¹ isindependently unsubstituted aryl. In embodiments, R¹¹ is independentlyunsubstituted heteroaryl. In embodiments, R¹¹ is independentlysubstituted or unsubstituted C₁-C₆ alkyl. In embodiments, R¹¹ isindependently substituted or unsubstituted 2 to 6 membered heteroalkyl.In embodiments, R¹¹ is independently substituted or unsubstituted C₃-C₈cycloalkyl. In embodiments, R¹¹ is independently substituted orunsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R¹¹ isindependently substituted or unsubstituted C₆ aryl. In embodiments, R¹¹is independently substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R¹¹ is independently substituted C₁-C₆alkyl. In embodiments, R¹¹ is independently substituted 2 to 6 memberedheteroalkyl. In embodiments, R¹¹ is independently substituted C₃-C₈cycloalkyl. In embodiments, R¹¹ is independently substituted 3 to 8membered heterocycloalkyl. In embodiments, R¹¹ is independentlysubstituted C₆ aryl. In embodiments, R¹¹ is independently substituted 5to 6 membered heteroaryl. In embodiments, R¹¹ is independentlyunsubstituted C₁-C₆ alkyl. In embodiments, R¹¹ is independentlyunsubstituted 2 to 6 membered heteroalkyl. In embodiments, R¹¹ isindependently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R¹¹ isindependently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R¹¹ is independently unsubstituted C₆ aryl. In embodiments,R¹¹ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, each R¹² is independently hydrogen. In embodiments, eachR¹² is independently —CX₃. In embodiments, each R¹² is independently—CN. In embodiments, each R¹² is independently —COOH. In embodiments,each R¹² is independently —CONH₂. In embodiments, each R¹² isindependently —CHX₂. In embodiments, each R¹² is independently —CH₂X. Inembodiments, each R¹² is independently substituted or unsubstitutedalkyl. In embodiments, each R¹² is independently substituted orunsubstituted heteroalkyl. In embodiments, each R¹² is independentlysubstituted or unsubstituted cycloalkyl. In embodiments, each R¹² isindependently substituted or unsubstituted heterocycloalkyl. Inembodiments, each R¹² is independently substituted or unsubstitutedaryl. In embodiments, each R¹² is independently or substituted orunsubstituted heteroaryl. In embodiments, R¹² is independentlysubstituted alkyl. In embodiments, R¹² is independently substitutedheteroalkyl. In embodiments, R¹² is independently substitutedcycloalkyl. In embodiments, R¹² is independently substitutedheterocycloalkyl. In embodiments, R¹² is independently substituted aryl.In embodiments, R¹² is independently substituted heteroaryl. Inembodiments, R¹² is independently unsubstituted alkyl. In embodiments,R¹² is independently unsubstituted heteroalkyl. In embodiments, R¹² isindependently unsubstituted cycloalkyl. In embodiments, R¹² isindependently unsubstituted heterocycloalkyl. In embodiments, R¹² isindependently unsubstituted aryl. In embodiments, R¹² is independentlyunsubstituted heteroaryl. In embodiments, R¹² is independentlysubstituted or unsubstituted C₁-C₆ alkyl. In embodiments, R¹² isindependently substituted or unsubstituted 2 to 6 membered heteroalkyl.In embodiments, R¹² is independently substituted or unsubstituted C₃-C₈cycloalkyl. In embodiments, R¹² is independently substituted orunsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R¹² isindependently substituted or unsubstituted C₆ aryl. In embodiments, R¹²is independently substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R¹² is independently substituted C₁-C₆alkyl. In embodiments, R¹² is independently substituted 2 to 6 memberedheteroalkyl. In embodiments, R¹² is independently substituted C₃-C₈cycloalkyl. In embodiments, R¹² is independently substituted 3 to 8membered heterocycloalkyl. In embodiments, R¹² is independentlysubstituted C₆ aryl. In embodiments, R¹² is independently substituted 5to 6 membered heteroaryl. In embodiments, R¹² is independentlyunsubstituted C₁-C₆ alkyl. In embodiments, R¹² is independentlyunsubstituted 2 to 6 membered heteroalkyl. In embodiments, R¹² isindependently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R¹² isindependently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R¹² is independently unsubstituted C₆ aryl. In embodiments,R¹² is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, each R¹³ is independently hydrogen. In embodiments, eachR¹³ is independently —CX₃. In embodiments, each R¹³ is independently—CN. In embodiments, each R¹³ is independently —COOH. In embodiments,each R¹³ is independently —CONH₂. In embodiments, each R¹³ isindependently —CHX₂. In embodiments, each R¹³ is independently —CH₂X. Inembodiments, each R¹³ is independently substituted or unsubstitutedalkyl. In embodiments, each R¹³ is independently substituted orunsubstituted heteroalkyl. In embodiments, each R¹³ is independentlysubstituted or unsubstituted cycloalkyl. In embodiments, each R¹³ isindependently substituted or unsubstituted heterocycloalkyl. Inembodiments, each R¹³ is independently substituted or unsubstitutedaryl. In embodiments, each R¹³ is independently or substituted orunsubstituted heteroaryl. In embodiments, R¹³ is independentlysubstituted alkyl. In embodiments, R¹³ is independently substitutedheteroalkyl. In embodiments, R¹³ is independently substitutedcycloalkyl. In embodiments, R¹³ is independently substitutedheterocycloalkyl. In embodiments, R¹³ is independently substituted aryl.In embodiments, R¹³ is independently substituted heteroaryl. Inembodiments, R¹³ is independently unsubstituted alkyl. In embodiments,R¹³ is independently unsubstituted heteroalkyl. In embodiments, R¹³ isindependently unsubstituted cycloalkyl. In embodiments, R¹³ isindependently unsubstituted heterocycloalkyl. In embodiments, R¹³ isindependently unsubstituted aryl. In embodiments, R¹³ is independentlyunsubstituted heteroaryl. In embodiments, R¹³ is independentlysubstituted or unsubstituted C₁-C₆ alkyl. In embodiments, R¹³ isindependently substituted or unsubstituted 2 to 6 membered heteroalkyl.In embodiments, R¹³ is independently substituted or unsubstituted C₃-C₈cycloalkyl. In embodiments, R¹³ is independently substituted orunsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R¹³ isindependently substituted or unsubstituted C₆ aryl. In embodiments, R¹³is independently substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R¹³ is independently substituted C₁-C₆alkyl. In embodiments, R¹³ is independently substituted 2 to 6 memberedheteroalkyl. In embodiments, R¹³ is independently substituted C₃-C₈cycloalkyl. In embodiments, R¹³ is independently substituted 3 to 8membered heterocycloalkyl. In embodiments, R¹³ is independentlysubstituted C₆ aryl. In embodiments, R¹³ is independently substituted 5to 6 membered heteroaryl. In embodiments, R¹³ is independentlyunsubstituted C₁-C₆ alkyl. In embodiments, R¹³ is independentlyunsubstituted 2 to 6 membered heteroalkyl. In embodiments, R¹³ isindependently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R¹³ isindependently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R¹³ is independently unsubstituted C₆ aryl. In embodiments,R¹³ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, each R¹⁴ is independently hydrogen. In embodiments, eachR¹⁴ is independently —CX₃. In embodiments, each R¹⁴ is independently—CN. In embodiments, each R¹⁴ is independently —COOH. In embodiments,each R¹⁴ is independently —CONH₂. In embodiments, each R¹⁴ isindependently —CHX₂. In embodiments, each R¹⁴ is independently —CH₂X. Inembodiments, each R¹⁴ is independently substituted or unsubstitutedalkyl. In embodiments, each R¹⁴ is independently substituted orunsubstituted heteroalkyl. In embodiments, each R¹⁴ is independentlysubstituted or unsubstituted cycloalkyl. In embodiments, each R¹⁴ isindependently substituted or unsubstituted heterocycloalkyl. Inembodiments, each R¹⁴ is independently substituted or unsubstitutedaryl. In embodiments, each R¹⁴ is independently or substituted orunsubstituted heteroaryl. In embodiments, R¹⁴ is independentlysubstituted alkyl. In embodiments, R¹⁴ is independently substitutedheteroalkyl. In embodiments, R¹⁴ is independently substitutedcycloalkyl. In embodiments, R¹⁴ is independently substitutedheterocycloalkyl. In embodiments, R¹⁴ is independently substituted aryl.In embodiments, R¹⁴ is independently substituted heteroaryl. Inembodiments, R¹⁴ is independently unsubstituted alkyl. In embodiments,R¹⁴ is independently unsubstituted heteroalkyl. In embodiments, R¹⁴ isindependently unsubstituted cycloalkyl. In embodiments, R¹⁴ isindependently unsubstituted heterocycloalkyl. In embodiments, R¹⁴ isindependently unsubstituted aryl. In embodiments, R¹⁴ is independentlyunsubstituted heteroaryl. In embodiments, R¹⁴ is independentlysubstituted or unsubstituted C₁-C₆ alkyl. In embodiments, R¹⁴ isindependently substituted or unsubstituted 2 to 6 membered heteroalkyl.In embodiments, R¹⁴ is independently substituted or unsubstituted C₃-C₈cycloalkyl. In embodiments, R¹⁴ is independently substituted orunsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R¹⁴ isindependently substituted or unsubstituted C₆ aryl. In embodiments, R¹⁴is independently substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R¹⁴ is independently substituted C₁-C₆alkyl. In embodiments, R¹⁴ is independently substituted 2 to 6 memberedheteroalkyl. In embodiments, R¹⁴ is independently substituted C₃-C₈cycloalkyl. In embodiments, R¹⁴ is independently substituted 3 to 8membered heterocycloalkyl. In embodiments, R¹⁴ is independentlysubstituted C₆ aryl. In embodiments, R¹⁴ is independently substituted 5to 6 membered heteroaryl. In embodiments, R¹⁴ is independentlyunsubstituted C₁-C₆ alkyl. In embodiments, R¹⁴ is independentlyunsubstituted 2 to 6 membered heteroalkyl. In embodiments, R¹⁴ isindependently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R¹⁴ isindependently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R¹⁴ is independently unsubstituted C₆ aryl. In embodiments,R¹⁴ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, each R¹⁵ is independently hydrogen. In embodiments, eachR¹⁵ is independently —CX₃. In embodiments, each R¹⁵ is independently—CN. In embodiments, each R¹⁵ is independently —COOH. In embodiments,each R¹⁵ is independently —CONH₂. In embodiments, each R¹⁵ isindependently —CHX₂. In embodiments, each R¹⁵ is independently —CH₂X. Inembodiments, each R¹⁵ is independently substituted or unsubstitutedalkyl. In embodiments, each R¹⁵ is independently substituted orunsubstituted heteroalkyl. In embodiments, each R¹⁵ is independentlysubstituted or unsubstituted cycloalkyl. In embodiments, each R¹⁵ isindependently substituted or unsubstituted heterocycloalkyl. Inembodiments, each R¹⁵ is independently substituted or unsubstitutedaryl. In embodiments, each R¹⁵ is independently or substituted orunsubstituted heteroaryl. In embodiments, R¹⁵ is independentlysubstituted alkyl. In embodiments, R¹⁵ is independently substitutedheteroalkyl. In embodiments, R¹⁵ is independently substitutedcycloalkyl. In embodiments, R¹⁵ is independently substitutedheterocycloalkyl. In embodiments, R¹⁵ is independently substituted aryl.In embodiments, R¹⁵ is independently substituted heteroaryl. Inembodiments, R¹⁵ is independently unsubstituted alkyl. In embodiments,R¹⁵ is independently unsubstituted heteroalkyl. In embodiments, R¹⁵ isindependently unsubstituted cycloalkyl. In embodiments, R¹⁵ isindependently unsubstituted heterocycloalkyl. In embodiments, R¹⁵ isindependently unsubstituted aryl. In embodiments, R¹⁵ is independentlyunsubstituted heteroaryl. In embodiments, R¹⁵ is independentlysubstituted or unsubstituted C₁-C₆ alkyl. In embodiments, R¹⁵ isindependently substituted or unsubstituted 2 to 6 membered heteroalkyl.In embodiments, R¹⁵ is independently substituted or unsubstituted C₃-C₈cycloalkyl. In embodiments, R¹⁵ is independently substituted orunsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R¹⁵ isindependently substituted or unsubstituted C₆ aryl. In embodiments, R¹⁵is independently substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R¹⁵ is independently substituted C₁-C₆alkyl. In embodiments, R¹⁵ is independently substituted 2 to 6 memberedheteroalkyl. In embodiments, R¹⁵ is independently substituted C₃-C₈cycloalkyl. In embodiments, R¹⁵ is independently substituted 3 to 8membered heterocycloalkyl. In embodiments, R¹⁵ is independentlysubstituted C₆ aryl. In embodiments, R¹⁵ is independently substituted 5to 6 membered heteroaryl. In embodiments, R¹⁵ is independentlyunsubstituted C₁-C₆ alkyl. In embodiments, R¹⁵ is independentlyunsubstituted 2 to 6 membered heteroalkyl. In embodiments, R¹⁵ isindependently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R¹⁵ isindependently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R¹⁵ is independently unsubstituted C₆ aryl. In embodiments,R¹⁵ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, each R¹⁶ is independently hydrogen. In embodiments, eachR¹⁶ is independently —CX₃. In embodiments, each R¹⁶ is independently—CN. In embodiments, each R¹⁶ is independently —COOH. In embodiments,each R¹⁶ is independently —CONH₂. In embodiments, each R¹⁶ isindependently —CHX₂. In embodiments, each R¹⁶ is independently —CH₂X. Inembodiments, each R¹⁶ is independently substituted or unsubstitutedalkyl. In embodiments, each R¹⁶ is independently substituted orunsubstituted heteroalkyl. In embodiments, each R¹⁶ is independentlysubstituted or unsubstituted cycloalkyl. In embodiments, each R¹⁶ isindependently substituted or unsubstituted heterocycloalkyl. Inembodiments, each R¹⁶ is independently substituted or unsubstitutedaryl. In embodiments, each R¹⁶ is independently or substituted orunsubstituted heteroaryl. In embodiments, R¹⁶ is independentlysubstituted alkyl. In embodiments, R¹⁶ is independently substitutedheteroalkyl. In embodiments, R¹⁶ is independently substitutedcycloalkyl. In embodiments, R¹⁶ is independently substitutedheterocycloalkyl. In embodiments, R¹⁶ is independently substituted aryl.In embodiments, R¹⁶ is independently substituted heteroaryl. Inembodiments, R¹⁶ is independently unsubstituted alkyl. In embodiments,R¹⁶ is independently unsubstituted heteroalkyl. In embodiments, R¹⁶ isindependently unsubstituted cycloalkyl. In embodiments, R¹⁶ isindependently unsubstituted heterocycloalkyl. In embodiments, R¹⁶ isindependently unsubstituted aryl. In embodiments, R¹⁶ is independentlyunsubstituted heteroaryl. In embodiments, R¹⁶ is independentlysubstituted or unsubstituted C₁-C₆ alkyl. In embodiments, R¹⁶ isindependently substituted or unsubstituted 2 to 6 membered heteroalkyl.In embodiments, R¹⁶ is independently substituted or unsubstituted C₃-C₈cycloalkyl. In embodiments, R¹⁶ is independently substituted orunsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R¹⁶ isindependently substituted or unsubstituted C₆ aryl. In embodiments, R¹⁶is independently substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R¹⁶ is independently substituted C₁-C₆alkyl. In embodiments, R¹⁶ is independently substituted 2 to 6 memberedheteroalkyl. In embodiments, R¹⁶ is independently substituted C₃-C₈cycloalkyl. In embodiments, R¹⁶ is independently substituted 3 to 8membered heterocycloalkyl. In embodiments, R¹⁶ is independentlysubstituted C₆ aryl. In embodiments, R¹⁶ is independently substituted 5to 6 membered heteroaryl. In embodiments, R¹⁶ is independentlyunsubstituted C₁-C₆ alkyl. In embodiments, R¹⁶ is independentlyunsubstituted 2 to 6 membered heteroalkyl. In embodiments, R¹⁶ isindependently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R¹⁶ isindependently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R¹⁶ is independently unsubstituted C₆ aryl. In embodiments,R¹⁶ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, each R¹⁷ is independently hydrogen. In embodiments, eachR¹⁷ is independently —CX₃. In embodiments, each R¹⁷ is independently—CN. In embodiments, each R¹⁷ is independently —COOH. In embodiments,each R¹⁷ is independently —CONH₂. In embodiments, each R¹⁷ isindependently —CHX₂. In embodiments, each R¹⁷ is independently —CH₂X. Inembodiments, each R¹⁷ is independently substituted or unsubstitutedalkyl. In embodiments, each R¹⁷ is independently substituted orunsubstituted heteroalkyl. In embodiments, each R¹⁷ is independentlysubstituted or unsubstituted cycloalkyl. In embodiments, each R¹⁷ isindependently substituted or unsubstituted heterocycloalkyl. Inembodiments, each R¹⁷ is independently substituted or unsubstitutedaryl. In embodiments, each R¹⁷ is independently or substituted orunsubstituted heteroaryl. In embodiments, R¹⁷ is independentlysubstituted alkyl. In embodiments, R¹⁷ is independently substitutedheteroalkyl. In embodiments, R¹⁷ is independently substitutedcycloalkyl. In embodiments, R⁷ is independently substitutedheterocycloalkyl. In embodiments, R¹⁷ is independently substituted aryl.In embodiments, R¹⁷ is independently substituted heteroaryl. Inembodiments, R¹⁷ is independently unsubstituted alkyl. In embodiments,R¹⁷ is independently unsubstituted heteroalkyl. In embodiments, R¹⁷ isindependently unsubstituted cycloalkyl. In embodiments, R¹⁷ isindependently unsubstituted heterocycloalkyl. In embodiments, R¹⁷ isindependently unsubstituted aryl. In embodiments, R¹⁷ is independentlyunsubstituted heteroaryl. In embodiments, R¹⁷ is independentlysubstituted or unsubstituted C₁-C₆ alkyl. In embodiments, R¹⁷ isindependently substituted or unsubstituted 2 to 6 membered heteroalkyl.In embodiments, R¹⁷ is independently substituted or unsubstituted C₃-C₈cycloalkyl. In embodiments, R¹⁷ is independently substituted orunsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R¹⁷ isindependently substituted or unsubstituted C₆ aryl. In embodiments, R¹⁷is independently substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R¹⁷ is independently substituted C₁-C₆alkyl. In embodiments, R¹⁷ is independently substituted 2 to 6 memberedheteroalkyl. In embodiments, R¹⁷ is independently substituted C₃-C₈cycloalkyl. In embodiments, R¹⁷ is independently substituted 3 to 8membered heterocycloalkyl. In embodiments, R¹⁷ is independentlysubstituted C₆ aryl. In embodiments, R¹⁷ is independently substituted 5to 6 membered heteroaryl. In embodiments, R¹⁷ is independentlyunsubstituted C₁-C₆ alkyl. In embodiments, R¹⁷ is independentlyunsubstituted 2 to 6 membered heteroalkyl. In embodiments, R¹⁷ isindependently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R¹⁷ isindependently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R¹⁷ is independently unsubstituted C₆ aryl. In embodiments,R¹⁷ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, each R⁸ is independently hydrogen. In embodiments, eachR⁸ is independently —CX₃. In embodiments, each R¹⁸ is independently —CN.In embodiments, each R¹⁸ is independently —COOH. In embodiments, eachR¹⁸ is independently —CONH₂. In embodiments, each R¹⁸ is independently—CHX₂. In embodiments, each R¹⁸ is independently —CH₂X. In embodiments,each R¹⁸ is independently substituted or unsubstituted alkyl. Inembodiments, each R¹⁸ is independently substituted or unsubstitutedheteroalkyl. In embodiments, each R¹⁸ is independently substituted orunsubstituted cycloalkyl. In embodiments, each R¹⁸ is independentlysubstituted or unsubstituted heterocycloalkyl. In embodiments, each R¹⁸is independently substituted or unsubstituted aryl. In embodiments, eachR¹⁸ is independently or substituted or unsubstituted heteroaryl. Inembodiments, R¹⁸ is independently substituted alkyl. In embodiments, R¹⁸is independently substituted heteroalkyl. In embodiments, R¹⁸ isindependently substituted cycloalkyl. In embodiments, R¹⁸ isindependently substituted heterocycloalkyl. In embodiments, R¹⁸ isindependently substituted aryl. In embodiments, R¹⁸ is independentlysubstituted heteroaryl. In embodiments, R¹⁸ is independentlyunsubstituted alkyl. In embodiments, R¹⁸ is independently unsubstitutedheteroalkyl. In embodiments, R¹⁸ is independently unsubstitutedcycloalkyl. In embodiments, R¹⁸ is independently unsubstitutedheterocycloalkyl. In embodiments, R¹⁸ is independently unsubstitutedaryl. In embodiments, R¹⁸ is independently unsubstituted heteroaryl. Inembodiments, R¹⁸ is independently substituted or unsubstituted C₁-C₆alkyl. In embodiments, R¹⁸ is independently substituted or unsubstituted2 to 6 membered heteroalkyl. In embodiments, R¹⁸ is independentlysubstituted or unsubstituted C₃-C₈ cycloalkyl. In embodiments, R⁸ isindependently substituted or unsubstituted 3 to 8 memberedheterocycloalkyl. In embodiments, R¹⁸ is independently substituted orunsubstituted C₆ aryl. In embodiments, R¹⁸ is independently substitutedor unsubstituted 5 to 6 membered heteroaryl. In embodiments, R¹⁸ isindependently substituted C₁-C₆ alkyl. In embodiments, R¹⁸ isindependently substituted 2 to 6 membered heteroalkyl. In embodiments,R¹⁸ is independently substituted C₃-C₈ cycloalkyl. In embodiments, R¹⁸is independently substituted 3 to 8 membered heterocycloalkyl. Inembodiments, R¹⁸ is independently substituted C₆ aryl. In embodiments,R¹⁸ is independently substituted 5 to 6 membered heteroaryl. Inembodiments, R¹⁸ is independently unsubstituted C₁-C₆ alkyl. Inembodiments, R¹⁸ is independently unsubstituted 2 to 6 memberedheteroalkyl. In embodiments, R¹⁸ is independently unsubstituted C₃-C₈cycloalkyl. In embodiments, R¹⁸ is independently unsubstituted 3 to 8membered heterocycloalkyl. In embodiments, R¹⁸ is independentlyunsubstituted C₆ aryl. In embodiments, R¹⁸ is independentlyunsubstituted 5 to 6 membered heteroaryl.

In embodiments, each R¹⁹ is independently hydrogen. In embodiments, eachR¹⁹ is independently —CX₃. In embodiments, each R¹⁹ is independently—CN. In embodiments, each R¹⁹ is independently —COOH. In embodiments,each R¹⁹ is independently —CONH₂. In embodiments, each R¹⁹ isindependently —CHX₂. In embodiments, each R¹⁹ is independently —CH₂X. Inembodiments, each R¹⁹ is independently substituted or unsubstitutedalkyl. In embodiments, each R¹⁹ is independently substituted orunsubstituted heteroalkyl. In embodiments, each R¹⁹ is independentlysubstituted or unsubstituted cycloalkyl. In embodiments, each R¹⁹ isindependently substituted or unsubstituted heterocycloalkyl. Inembodiments, each R¹⁹ is independently substituted or unsubstitutedaryl. In embodiments, each R¹⁹ is independently or substituted orunsubstituted heteroaryl. In embodiments, R¹⁹ is independentlysubstituted alkyl. In embodiments, R¹⁹ is independently substitutedheteroalkyl. In embodiments, R¹⁹ is independently substitutedcycloalkyl. In embodiments, R¹⁹ is independently substitutedheterocycloalkyl. In embodiments, R¹⁹ is independently substituted aryl.In embodiments, R¹⁹ is independently substituted heteroaryl. Inembodiments, R¹⁹ is independently unsubstituted alkyl. In embodiments,R¹⁹ is independently unsubstituted heteroalkyl. In embodiments, R¹⁹ isindependently unsubstituted cycloalkyl. In embodiments, R¹⁹ isindependently unsubstituted heterocycloalkyl. In embodiments, R¹⁹ isindependently unsubstituted aryl. In embodiments, R¹⁹ is independentlyunsubstituted heteroaryl. In embodiments, R¹⁹ is independentlysubstituted or unsubstituted C₁-C₆ alkyl. In embodiments, R¹⁹ isindependently substituted or unsubstituted 2 to 6 membered heteroalkyl.In embodiments, R¹⁹ is independently substituted or unsubstituted C₃-C₈cycloalkyl. In embodiments, R¹⁹ is independently substituted orunsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R¹⁹ isindependently substituted or unsubstituted C₆ aryl. In embodiments, R¹⁹is independently substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R¹⁹ is independently substituted C₁-C₆alkyl. In embodiments, R¹⁹ is independently substituted 2 to 6 memberedheteroalkyl. In embodiments, R¹⁹ is independently substituted C₃-C₈cycloalkyl. In embodiments, R¹⁹ is independently substituted 3 to 8membered heterocycloalkyl. In embodiments, R¹⁹ is independentlysubstituted C₆ aryl. In embodiments, R¹⁹ is independently substituted 5to 6 membered heteroaryl. In embodiments, R¹⁹ is independentlyunsubstituted C₁-C₆ alkyl. In embodiments, R¹⁹ is independentlyunsubstituted 2 to 6 membered heteroalkyl. In embodiments, R¹⁹ isindependently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R¹⁹ isindependently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R¹⁹ is independently unsubstituted C₆ aryl. In embodiments,R¹⁹ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, each R²⁰ is independently hydrogen. In embodiments, eachR²⁰ is independently —CX₃. In embodiments, each R²⁰ is independently—CN. In embodiments, each R²⁰ is independently —COOH. In embodiments,each R²⁰ is independently —CONH₂. In embodiments, each R²⁰ isindependently —CHX₂. In embodiments, each R²⁰ is independently —CH₂X. Inembodiments, each R²⁰ is independently substituted or unsubstitutedalkyl. In embodiments, each R²⁰ is independently substituted orunsubstituted heteroalkyl. In embodiments, each R²⁰ is independentlysubstituted or unsubstituted cycloalkyl. In embodiments, each R²⁰ isindependently substituted or unsubstituted heterocycloalkyl. Inembodiments, each R²⁰ is independently substituted or unsubstitutedaryl. In embodiments, each R²⁰ is independently or substituted orunsubstituted heteroaryl. In embodiments, R²⁰ is independentlysubstituted alkyl. In embodiments, R²⁰ is independently substitutedheteroalkyl. In embodiments, R²⁰ is independently substitutedcycloalkyl. In embodiments, R²⁰ is independently substitutedheterocycloalkyl. In embodiments, R²⁰ is independently substituted aryl.In embodiments, R²⁰ is independently substituted heteroaryl. Inembodiments, R²⁰ is independently unsubstituted alkyl. In embodiments,R²⁰ is independently unsubstituted heteroalkyl. In embodiments, R²⁰ isindependently unsubstituted cycloalkyl. In embodiments, R²⁰ isindependently unsubstituted heterocycloalkyl. In embodiments, R²⁰ isindependently unsubstituted aryl. In embodiments, R²⁰ is independentlyunsubstituted heteroaryl. In embodiments, R²⁰ is independentlysubstituted or unsubstituted C₁-C₆ alkyl. In embodiments, R²⁰ isindependently substituted or unsubstituted 2 to 6 membered heteroalkyl.In embodiments, R²⁰ is independently substituted or unsubstituted C₃-C₈cycloalkyl. In embodiments, R²⁰ is independently substituted orunsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R²⁰ isindependently substituted or unsubstituted C₆ aryl. In embodiments, R²⁰is independently substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R²⁰ is independently substituted C₁-C₆alkyl. In embodiments, R²⁰ is independently substituted 2 to 6 memberedheteroalkyl. In embodiments, R²⁰ is independently substituted C₃-C₈cycloalkyl. In embodiments, R²⁰ is independently substituted 3 to 8membered heterocycloalkyl. In embodiments, R²⁰ is independentlysubstituted C₆ aryl. In embodiments, R²⁰ is independently substituted 5to 6 membered heteroaryl. In embodiments, R²⁰ is independentlyunsubstituted C₁-C₆ alkyl. In embodiments, R²⁰ is independentlyunsubstituted 2 to 6 membered heteroalkyl. In embodiments, R²⁰ isindependently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R²⁰ isindependently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R²⁰ is independently unsubstituted C₆ aryl. In embodiments,R²⁰ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, each R²¹ is independently hydrogen. In embodiments, eachR²¹ is independently —CX₃. In embodiments, each R²¹ is independently—CN. In embodiments, each R²¹ is independently —COOH. In embodiments,each R²¹ is independently —CONH₂. In embodiments, each R²¹ isindependently —CHX₂. In embodiments, each R²¹ is independently —CH₂X. Inembodiments, each R²¹ is independently substituted or unsubstitutedalkyl. In embodiments, each R²¹ is independently substituted orunsubstituted heteroalkyl. In embodiments, each R²¹ is independentlysubstituted or unsubstituted cycloalkyl. In embodiments, each R²¹ isindependently substituted or unsubstituted heterocycloalkyl. Inembodiments, each R²¹ is independently substituted or unsubstitutedaryl. In embodiments, each R²¹ is independently or substituted orunsubstituted heteroaryl. In embodiments, R²¹ is independentlysubstituted alkyl. In embodiments, R²¹ is independently substitutedheteroalkyl. In embodiments, R²¹ is independently substitutedcycloalkyl. In embodiments, R²¹ is independently substitutedheterocycloalkyl. In embodiments, R²¹ is independently substituted aryl.In embodiments, R²¹ is independently substituted heteroaryl. Inembodiments, R²¹ is independently unsubstituted alkyl. In embodiments,R²¹ is independently unsubstituted heteroalkyl. In embodiments, R²¹ isindependently unsubstituted cycloalkyl. In embodiments, R²¹ isindependently unsubstituted heterocycloalkyl. In embodiments, R²¹ isindependently unsubstituted aryl. In embodiments, R²¹ is independentlyunsubstituted heteroaryl. In embodiments, R²¹ is independentlysubstituted or unsubstituted C₁-C₆ alkyl. In embodiments, R²¹ isindependently substituted or unsubstituted 2 to 6 membered heteroalkyl.In embodiments, R²¹ is independently substituted or unsubstituted C₃-C₈cycloalkyl. In embodiments, R²¹ is independently substituted orunsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R²¹ isindependently substituted or unsubstituted C₆ aryl. In embodiments, R²¹is independently substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R²¹ is independently substituted C₁-C₆alkyl. In embodiments, R²¹ is independently substituted 2 to 6 memberedheteroalkyl. In embodiments, R²¹ is independently substituted C₃-C₈cycloalkyl. In embodiments, R²¹ is independently substituted 3 to 8membered heterocycloalkyl. In embodiments, R²¹ is independentlysubstituted C₆ aryl. In embodiments, R²¹ is independently substituted 5to 6 membered heteroaryl. In embodiments, R²¹ is independentlyunsubstituted C₁-C₆ alkyl. In embodiments, R²¹ is independentlyunsubstituted 2 to 6 membered heteroalkyl. In embodiments, R²¹ isindependently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R²¹ isindependently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R²¹ is independently unsubstituted C₆ aryl. In embodiments,R²¹ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, each R²² is independently hydrogen. In embodiments, eachR²² is independently —CX₃. In embodiments, each R²² is independently—CN. In embodiments, each R²² is independently —COOH. In embodiments,each R²² is independently —CONH₂. In embodiments, each R²² isindependently —CHX₂. In embodiments, each R²² is independently —CH₂X. Inembodiments, each R²² is independently substituted or unsubstitutedalkyl. In embodiments, each R²² is independently substituted orunsubstituted heteroalkyl. In embodiments, each R²² is independentlysubstituted or unsubstituted cycloalkyl. In embodiments, each R²² isindependently substituted or unsubstituted heterocycloalkyl. Inembodiments, each R²² is independently substituted or unsubstitutedaryl. In embodiments, each R²² is independently or substituted orunsubstituted heteroaryl. In embodiments, R²² is independentlysubstituted alkyl. In embodiments, R²² is independently substitutedheteroalkyl. In embodiments, R²² is independently substitutedcycloalkyl. In embodiments, R²² is independently substitutedheterocycloalkyl. In embodiments, R²² is independently substituted aryl.In embodiments, R²² is independently substituted heteroaryl. Inembodiments, R²² is independently unsubstituted alkyl. In embodiments,R²² is independently unsubstituted heteroalkyl. In embodiments, R²² isindependently unsubstituted cycloalkyl. In embodiments, R²² isindependently unsubstituted heterocycloalkyl. In embodiments, R²² isindependently unsubstituted aryl. In embodiments, R²² is independentlyunsubstituted heteroaryl. In embodiments, R²² is independentlysubstituted or unsubstituted C₁-C₆ alkyl. In embodiments, R²² isindependently substituted or unsubstituted 2 to 6 membered heteroalkyl.In embodiments, R²² is independently substituted or unsubstituted C₃-C₈cycloalkyl. In embodiments, R²² is independently substituted orunsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R²² isindependently substituted or unsubstituted C₆ aryl. In embodiments, R²²is independently substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R²² is independently substituted C₁-C₆alkyl. In embodiments, R²² is independently substituted 2 to 6 memberedheteroalkyl. In embodiments, R²² is independently substituted C₃-C₈cycloalkyl. In embodiments, R²² is independently substituted 3 to 8membered heterocycloalkyl. In embodiments, R²² is independentlysubstituted C₆ aryl. In embodiments, R²² is independently substituted 5to 6 membered heteroaryl. In embodiments, R²² is independentlyunsubstituted C₁-C₆ alkyl. In embodiments, R²² is independentlyunsubstituted 2 to 6 membered heteroalkyl. In embodiments, R²² isindependently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R²² isindependently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R²² is independently unsubstituted C₆ aryl. In embodiments,R²² is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, each R²³ is independently hydrogen. In embodiments, eachR²³ is independently —CX₃. In embodiments, each R²³ is independently—CN. In embodiments, each R²³ is independently —COOH. In embodiments,each R²³ is independently —CONH₂. In embodiments, each R²³ isindependently —CHX₂. In embodiments, each R²³ is independently —CH₂X. Inembodiments, each R²³ is independently substituted or unsubstitutedalkyl. In embodiments, each R²³ is independently substituted orunsubstituted heteroalkyl. In embodiments, each R²³ is independentlysubstituted or unsubstituted cycloalkyl. In embodiments, each R²³ isindependently substituted or unsubstituted heterocycloalkyl. Inembodiments, each R²³ is independently substituted or unsubstitutedaryl. In embodiments, each R²³ is independently or substituted orunsubstituted heteroaryl. In embodiments, R²³ is independentlysubstituted alkyl. In embodiments, R²³ is independently substitutedheteroalkyl. In embodiments, R²³ is independently substitutedcycloalkyl. In embodiments, R²³ is independently substitutedheterocycloalkyl. In embodiments, R²³ is independently substituted aryl.In embodiments, R²³ is independently substituted heteroaryl. Inembodiments, R²³ is independently unsubstituted alkyl. In embodiments,R²³ is independently unsubstituted heteroalkyl. In embodiments, R²³ isindependently unsubstituted cycloalkyl. In embodiments, R²³ isindependently unsubstituted heterocycloalkyl. In embodiments, R²³ isindependently unsubstituted aryl. In embodiments, R²³ is independentlyunsubstituted heteroaryl. In embodiments, R²³ is independentlysubstituted or unsubstituted C₁-C₆ alkyl. In embodiments, R²³ isindependently substituted or unsubstituted 2 to 6 membered heteroalkyl.In embodiments, R²³ is independently substituted or unsubstituted C₃-C₈cycloalkyl. In embodiments, R²³ is independently substituted orunsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R²³ isindependently substituted or unsubstituted C₆ aryl. In embodiments, R²³is independently substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R²³ is independently substituted C₁-C₆alkyl. In embodiments, R²³ is independently substituted 2 to 6 memberedheteroalkyl. In embodiments, R²³ is independently substituted C₃-C₈cycloalkyl. In embodiments, R²³ is independently substituted 3 to 8membered heterocycloalkyl. In embodiments, R²³ is independentlysubstituted C₆ aryl. In embodiments, R²³ is independently substituted 5to 6 membered heteroaryl. In embodiments, R²³ is independentlyunsubstituted C₁-C₆ alkyl. In embodiments, R²³ is independentlyunsubstituted 2 to 6 membered heteroalkyl. In embodiments, R²³ isindependently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R²³ isindependently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R²³ is independently unsubstituted C₆ aryl. In embodiments,R²³ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, each R²⁴ is independently hydrogen. In embodiments, eachR²⁴ is independently —CX₃. In embodiments, each R²⁴ is independently—CN. In embodiments, each R²⁴ is independently —COOH. In embodiments,each R²⁴ is independently —CONH₂. In embodiments, each R²⁴ isindependently —CHX₂. In embodiments, each R²³ is independently —CH₂X. Inembodiments, each R²⁴ is independently substituted or unsubstitutedalkyl. In embodiments, each R²⁴ is independently substituted orunsubstituted heteroalkyl. In embodiments, each R²⁴ is independentlysubstituted or unsubstituted cycloalkyl. In embodiments, each R²⁴ isindependently substituted or unsubstituted heterocycloalkyl. Inembodiments, each R²⁴ is independently substituted or unsubstitutedaryl. In embodiments, each R²⁴ is independently or substituted orunsubstituted heteroaryl. In embodiments, R²⁴ is independentlysubstituted alkyl. In embodiments, R²⁴ is independently substitutedheteroalkyl. In embodiments, R²⁴ is independently substitutedcycloalkyl. In embodiments, R²⁴ is independently substitutedheterocycloalkyl. In embodiments, R²⁴ is independently substituted aryl.In embodiments, R²⁴ is independently substituted heteroaryl. Inembodiments, R²⁴ is independently unsubstituted alkyl. In embodiments,R²⁴ is independently unsubstituted heteroalkyl. In embodiments, R²⁴ isindependently unsubstituted cycloalkyl. In embodiments, R²⁴ isindependently unsubstituted heterocycloalkyl. In embodiments, R²⁴ isindependently unsubstituted aryl. In embodiments, R²⁴ is independentlyunsubstituted heteroaryl. In embodiments, R²⁴ is independentlysubstituted or unsubstituted C₁-C₆ alkyl. In embodiments, R²⁴ isindependently substituted or unsubstituted 2 to 6 membered heteroalkyl.In embodiments, R²⁴ is independently substituted or unsubstituted C₃-C₈cycloalkyl. In embodiments, R²⁴ is independently substituted orunsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R²⁴ isindependently substituted or unsubstituted C₆ aryl. In embodiments, R²⁴is independently substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R²⁴ is independently substituted C₁-C₆alkyl. In embodiments, R²⁴ is independently substituted 2 to 6 memberedheteroalkyl. In embodiments, R²⁴ is independently substituted C₃-C₈cycloalkyl. In embodiments, R²⁴ is independently substituted 3 to 8membered heterocycloalkyl. In embodiments, R²⁴ is independentlysubstituted C₆ aryl. In embodiments, R²⁴ is independently substituted 5to 6 membered heteroaryl. In embodiments, R²⁴ is independentlyunsubstituted C₁-C₆ alkyl. In embodiments, R²⁴ is independentlyunsubstituted 2 to 6 membered heteroalkyl. In embodiments, R²⁴ isindependently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R²⁴ isindependently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R²⁴ is independently unsubstituted C₆ aryl. In embodiments,R²⁴ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, each R²⁵ is independently hydrogen. In embodiments, eachR²⁵ is independently —CX₃. In embodiments, each R²⁵ is independently—CN. In embodiments, each R²⁵ is independently —COOH. In embodiments,each R²⁵ is independently —CONH₂. In embodiments, each R²⁵ isindependently —CHX₂. In embodiments, each R²⁵ is independently —CH₂X. Inembodiments, each R²⁵ is independently substituted or unsubstitutedalkyl. In embodiments, each R²⁵ is independently substituted orunsubstituted heteroalkyl. In embodiments, each R²⁵ is independentlysubstituted or unsubstituted cycloalkyl. In embodiments, each R²⁵ isindependently substituted or unsubstituted heterocycloalkyl. Inembodiments, each R²⁵ is independently substituted or unsubstitutedaryl. In embodiments, each R²⁵ is independently or substituted orunsubstituted heteroaryl. In embodiments, R²⁵ is independentlysubstituted alkyl. In embodiments, R²⁵ is independently substitutedheteroalkyl. In embodiments, R²⁵ is independently substitutedcycloalkyl. In embodiments, R²⁵ is independently substitutedheterocycloalkyl. In embodiments, R²⁵ is independently substituted aryl.In embodiments, R²⁵ is independently substituted heteroaryl. Inembodiments, R²⁵ is independently unsubstituted alkyl. In embodiments,R²⁵ is independently unsubstituted heteroalkyl. In embodiments, R²⁵ isindependently unsubstituted cycloalkyl. In embodiments, R²⁵ isindependently unsubstituted heterocycloalkyl. In embodiments, R²⁵ isindependently unsubstituted aryl. In embodiments, R²⁵ is independentlyunsubstituted heteroaryl. In embodiments, R²⁵ is independentlysubstituted or unsubstituted C₁-C₆ alkyl. In embodiments, R²⁵ isindependently substituted or unsubstituted 2 to 6 membered heteroalkyl.In embodiments, R²⁵ is independently substituted or unsubstituted C₃-C₈cycloalkyl. In embodiments, R²⁵ is independently substituted orunsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R²⁵ isindependently substituted or unsubstituted C₆ aryl. In embodiments, R²⁵is independently substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R²⁵ is independently substituted C₁-C₆alkyl. In embodiments, R²⁵ is independently substituted 2 to 6 memberedheteroalkyl. In embodiments, R²⁵ is independently substituted C₃-C₈cycloalkyl. In embodiments, R²⁵ is independently substituted 3 to 8membered heterocycloalkyl. In embodiments, R²⁵ is independentlysubstituted C₆ aryl. In embodiments, R²⁵ is independently substituted 5to 6 membered heteroaryl. In embodiments, R²⁵ is independentlyunsubstituted C₁-C₆ alkyl. In embodiments, R²⁵ is independentlyunsubstituted 2 to 6 membered heteroalkyl. In embodiments, R²⁵ isindependently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R²⁵ isindependently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R²⁵ is independently unsubstituted C₆ aryl. In embodiments,R²⁵ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, each R²⁶ is independently hydrogen. In embodiments, eachR²⁶ is independently —CX₃. In embodiments, each R²⁶ is independently—CN. In embodiments, each R²⁶ is independently —COOH. In embodiments,each R²⁶ is independently —CONH₂. In embodiments, each R²⁶ isindependently —CHX₂. In embodiments, each R²⁶ is independently —CH₂X. Inembodiments, each R²⁶ is independently substituted or unsubstitutedalkyl. In embodiments, each R²⁶ is independently substituted orunsubstituted heteroalkyl. In embodiments, each R²⁶ is independentlysubstituted or unsubstituted cycloalkyl. In embodiments, each R²⁶ isindependently substituted or unsubstituted heterocycloalkyl. Inembodiments, each R²⁶ is independently substituted or unsubstitutedaryl. In embodiments, each R²⁶ is independently or substituted orunsubstituted heteroaryl. In embodiments, R²⁶ is independentlysubstituted alkyl. In embodiments, R²⁶ is independently substitutedheteroalkyl. In embodiments, R²⁶ is independently substitutedcycloalkyl. In embodiments, R²⁶ is independently substitutedheterocycloalkyl. In embodiments, R²⁶ is independently substituted aryl.In embodiments, R²⁶ is independently substituted heteroaryl. Inembodiments, R²⁶ is independently unsubstituted alkyl. In embodiments,R²⁶ is independently unsubstituted heteroalkyl. In embodiments, R²⁶ isindependently unsubstituted cycloalkyl. In embodiments, R²⁶ isindependently unsubstituted heterocycloalkyl. In embodiments, R²⁶ isindependently unsubstituted aryl. In embodiments, R²⁶ is independentlyunsubstituted heteroaryl. In embodiments, R²⁶ is independentlysubstituted or unsubstituted C₁-C₆ alkyl. In embodiments, R²⁶ isindependently substituted or unsubstituted 2 to 6 membered heteroalkyl.In embodiments, R²⁶ is independently substituted or unsubstituted C₃-C₈cycloalkyl. In embodiments, R²⁶ is independently substituted orunsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R²⁶ isindependently substituted or unsubstituted C₆ aryl. In embodiments, R²⁶is independently substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R²⁶ is independently substituted C₁-C₆alkyl. In embodiments, R²⁶ is independently substituted 2 to 6 memberedheteroalkyl. In embodiments, R²⁶ is independently substituted C₃-C₈cycloalkyl. In embodiments, R²⁶ is independently substituted 3 to 8membered heterocycloalkyl. In embodiments, R²⁶ is independentlysubstituted C₆ aryl. In embodiments, R²⁶ is independently substituted 5to 6 membered heteroaryl. In embodiments, R²⁶ is independentlyunsubstituted C₁-C₆ alkyl. In embodiments, R²⁶ is independentlyunsubstituted 2 to 6 membered heteroalkyl. In embodiments, R²⁶ isindependently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R²⁶ isindependently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R²⁶ is independently unsubstituted C₆ aryl. In embodiments,R²⁶ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, each R²⁷ is independently hydrogen. In embodiments, eachR²⁷ is independently —CX₃. In embodiments, each R²⁷ is independently—CN. In embodiments, each R²⁷ is independently —COOH. In embodiments,each R²⁷ is independently —CONH₂. In embodiments, each R²⁷ isindependently —CHX₂. In embodiments, each R²⁷ is independently —CH₂X. Inembodiments, each R²⁷ is independently substituted or unsubstitutedalkyl. In embodiments, each R²⁷ is independently substituted orunsubstituted heteroalkyl. In embodiments, each R²⁷ is independentlysubstituted or unsubstituted cycloalkyl. In embodiments, each R²⁷ isindependently substituted or unsubstituted heterocycloalkyl. Inembodiments, each R²⁷ is independently substituted or unsubstitutedaryl. In embodiments, each R²⁷ is independently or substituted orunsubstituted heteroaryl. In embodiments, R²⁷ is independentlysubstituted alkyl. In embodiments, R²⁷ is independently substitutedheteroalkyl. In embodiments, R²⁷ is independently substitutedcycloalkyl. In embodiments, R²⁷ is independently substitutedheterocycloalkyl. In embodiments, R²⁷ is independently substituted aryl.In embodiments, R²⁷ is independently substituted heteroaryl. Inembodiments, R²⁷ is independently unsubstituted alkyl. In embodiments,R²⁷ is independently unsubstituted heteroalkyl. In embodiments, R²⁷ isindependently unsubstituted cycloalkyl. In embodiments, R²⁷ isindependently unsubstituted heterocycloalkyl. In embodiments, R²⁷ isindependently unsubstituted aryl. In embodiments, R²⁷ is independentlyunsubstituted heteroaryl. In embodiments, R²⁷ is independentlysubstituted or unsubstituted C₁-C₆ alkyl. In embodiments, R²⁷ isindependently substituted or unsubstituted 2 to 6 membered heteroalkyl.In embodiments, R²⁷ is independently substituted or unsubstituted C₃-C₈cycloalkyl. In embodiments, R²⁷ is independently substituted orunsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R²⁷ isindependently substituted or unsubstituted C₆ aryl. In embodiments, R²⁷is independently substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R²⁷ is independently substituted C₁-C₆alkyl. In embodiments, R²⁷ is independently substituted 2 to 6 memberedheteroalkyl. In embodiments, R²⁷ is independently substituted C₃-C₈cycloalkyl. In embodiments, R²⁷ is independently substituted 3 to 8membered heterocycloalkyl. In embodiments, R²⁷ is independentlysubstituted C₆ aryl. In embodiments, R²⁷ is independently substituted 5to 6 membered heteroaryl. In embodiments, R²⁷ is independentlyunsubstituted C₁-C₆ alkyl. In embodiments, R²⁷ is independentlyunsubstituted 2 to 6 membered heteroalkyl. In embodiments, R²⁷ isindependently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R²⁷ isindependently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R²⁷ is independently unsubstituted C₆ aryl. In embodiments,R²⁷ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, each R²⁸ is independently hydrogen. In embodiments, eachR²⁸ is independently —CX₃. In embodiments, each R²⁸ is independently—CN. In embodiments, each R²⁸ is independently —COOH. In embodiments,each R²⁸ is independently —CONH₂. In embodiments, each R²⁸ isindependently —CHX₂. In embodiments, each R²⁸ is independently —CH₂X. Inembodiments, each R²⁸ is independently substituted or unsubstitutedalkyl. In embodiments, each R²⁸ is independently substituted orunsubstituted heteroalkyl. In embodiments, each R²⁸ is independentlysubstituted or unsubstituted cycloalkyl. In embodiments, each R²⁸ isindependently substituted or unsubstituted heterocycloalkyl. Inembodiments, each R²⁸ is independently substituted or unsubstitutedaryl. In embodiments, each R²⁸ is independently or substituted orunsubstituted heteroaryl. In embodiments, R²⁸ is independentlysubstituted alkyl. In embodiments, R²⁸ is independently substitutedheteroalkyl. In embodiments, R²⁸ is independently substitutedcycloalkyl. In embodiments, R²⁸ is independently substitutedheterocycloalkyl. In embodiments, R²⁸ is independently substituted aryl.In embodiments, R²⁸ is independently substituted heteroaryl. Inembodiments, R²⁸ is independently unsubstituted alkyl. In embodiments,R²⁸ is independently unsubstituted heteroalkyl. In embodiments, R²⁸ isindependently unsubstituted cycloalkyl. In embodiments, R²⁸ isindependently unsubstituted heterocycloalkyl. In embodiments, R²⁸ isindependently unsubstituted aryl. In embodiments, R²⁸ is independentlyunsubstituted heteroaryl. In embodiments, R²⁸ is independentlysubstituted or unsubstituted C₁-C₆ alkyl. In embodiments, R²⁸ isindependently substituted or unsubstituted 2 to 6 membered heteroalkyl.In embodiments, R²⁸ is independently substituted or unsubstituted C₃-C₈cycloalkyl. In embodiments, R²⁸ is independently substituted orunsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R²⁸ isindependently substituted or unsubstituted C₆ aryl. In embodiments, R²⁸is independently substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R²⁸ is independently substituted C₁-C₆alkyl. In embodiments, R²⁸ is independently substituted 2 to 6 memberedheteroalkyl. In embodiments, R²⁸ is independently substituted C₃-C₈cycloalkyl. In embodiments, R²⁸ is independently substituted 3 to 8membered heterocycloalkyl. In embodiments, R²⁸ is independentlysubstituted C₆ aryl. In embodiments, R²⁸ is independently substituted 5to 6 membered heteroaryl. In embodiments, R²⁸ is independentlyunsubstituted C₁-C₆ alkyl. In embodiments, R²⁸ is independentlyunsubstituted 2 to 6 membered heteroalkyl. In embodiments, R²⁸ isindependently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R²⁸ isindependently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R²⁸ is independently unsubstituted C₆ aryl. In embodiments,R²⁸ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, R^(1A) is independently halogen. In embodiments, R^(1A)is independently —CN. In embodiments, R^(1A) is independently —OR^(1B).In embodiments, R^(1A) is independently —SR^(1B). In embodiments, R^(1A)is independently —NR^(1C)R^(1D). In embodiments, R^(1A) is independently—NR^(1C)C(O)R^(1B). In embodiments, R^(1A) is independently—C(O)NR^(1C)R^(1D). In embodiments, R^(1A) is independently —CO₂R^(1B).In embodiments, R^(1A) is independently substituted or unsubstitutedalkyl. In embodiments, R^(1A) is independently substituted orunsubstituted heteroalkyl. In embodiments, R^(1A) is independentlysubstituted alkyl. In embodiments, R^(1A) is independently substitutedheteroalkyl. In embodiments, R^(1A) is independently unsubstitutedalkyl. In embodiments, R^(1A) is independently unsubstitutedheteroalkyl.

In embodiments, R^(1B) is independently hydrogen. In embodiments, R^(1B)is independently substituted or unsubstituted alkyl. In embodiments,R^(1B) is independently substituted or unsubstituted heteroalkyl. Inembodiments, R^(1B) is independently substituted or unsubstitutedcycloalkyl. In embodiments, R^(1B) is independently substituted orunsubstituted heterocycloalkyl. In embodiments, R^(1B) is independentlysubstituted or unsubstituted aryl. In embodiments, R^(1B) isindependently substituted or unsubstituted heteroaryl. In embodiments,R^(1B) is independently substituted alkyl. In embodiments, R^(1B) isindependently substituted heteroalkyl. In embodiments, R^(1B) isindependently substituted cycloalkyl. In embodiments, R^(1B) isindependently substituted heterocycloalkyl. In embodiments, R^(1B) isindependently substituted aryl. In embodiments, R^(1B) is independentlysubstituted heteroaryl. In embodiments, R^(1B) is independentlyunsubstituted alkyl. In embodiments, R^(1B) is independentlyunsubstituted heteroalkyl. In embodiments, R^(1B) is independentlyunsubstituted cycloalkyl. In embodiments, R^(1B) is independentlyunsubstituted heterocycloalkyl. In embodiments, R^(1B) is independentlyunsubstituted aryl. In embodiments, R^(1B) is independentlyunsubstituted heteroaryl.

In embodiments, R^(1C) is independently hydrogen. In embodiments, R^(1C)is independently substituted or unsubstituted alkyl. In embodiments,R^(1C) is independently substituted or unsubstituted heteroalkyl. Inembodiments, R^(1C) is independently substituted or unsubstitutedcycloalkyl. In embodiments, R^(1C) is independently substituted orunsubstituted heterocycloalkyl. In embodiments, R^(1C) is independentlysubstituted or unsubstituted aryl. In embodiments, R^(1C) isindependently substituted or unsubstituted heteroaryl. In embodiments,R^(1C) is independently substituted alkyl. In embodiments, R^(1C) isindependently substituted heteroalkyl. In embodiments, R^(1C) isindependently substituted cycloalkyl. In embodiments, R^(1C) isindependently substituted heterocycloalkyl. In embodiments, R^(1C) isindependently substituted aryl. In embodiments, R^(1C) is independentlysubstituted heteroaryl. In embodiments, R^(1C) is independentlyunsubstituted alkyl. In embodiments, R^(1C) is independentlyunsubstituted heteroalkyl. In embodiments, R^(1C) is independentlyunsubstituted cycloalkyl. In embodiments, R^(1C) is independentlyunsubstituted heterocycloalkyl. In embodiments, R^(1C) is independentlyunsubstituted aryl. In embodiments, R^(1C) is independentlyunsubstituted heteroaryl.

In embodiments, R^(1D) is independently substituted or unsubstitutedalkyl. In embodiments, R^(1D) is independently substituted orunsubstituted heteroalkyl. In embodiments, R^(1D) is independentlysubstituted or unsubstituted cycloalkyl. In embodiments, R^(1D) isindependently substituted or unsubstituted heterocycloalkyl. Inembodiments, R^(1D) is independently substituted or unsubstituted aryl.In embodiments, R^(1D) is independently or substituted or unsubstitutedheteroaryl. In embodiments, R^(1D) is independently substituted alkyl.In embodiments, R^(1D) is independently substituted heteroalkyl. Inembodiments, R^(1D) is independently substituted cycloalkyl. Inembodiments, R^(1D) is independently substituted heterocycloalkyl. Inembodiments, R^(1D) is independently substituted aryl. In embodiments,R^(1D) is independently substituted heteroaryl. In embodiments, R^(1D)is independently unsubstituted alkyl. In embodiments, R^(1D) isindependently unsubstituted heteroalkyl. In embodiments, R^(1D) isindependently unsubstituted cycloalkyl. In embodiments, R^(1D) isindependently unsubstituted heterocycloalkyl. In embodiments, R^(1D) isindependently unsubstituted aryl. In embodiments, R^(1D) isindependently unsubstituted heteroaryl.

In embodiments, R^(1C) and R^(1D) attached to the same nitrogen atomoptionally combine to form a substituted or unsubstitutedheterocycloalkyl. In embodiments, R^(1C) and R^(1D) attached to the samenitrogen atom optionally combine to form a substituted heterocycloalkyl.In embodiments, R^(1C) and R^(1D) attached to the same nitrogen atomoptionally combine to form an unsubstituted heterocycloalkyl.

In embodiments, R^(2A) is independently —NR^(2B)R^(2C). In embodiments,R^(2A) is independently substituted or unsubstituted cycloalkyl. Inembodiments, R^(2A) is independently substituted or unsubstitutedheterocycloalkyl. In embodiments, R^(2A) is independently substituted orunsubstituted aryl. In embodiments, R^(2A) is independently substitutedor unsubstituted heteroaryl. In embodiments, R^(2A) is independentlysubstituted cycloalkyl. In embodiments, R^(2A) is independentlysubstituted heterocycloalkyl. In embodiments, R^(2A) is independentlysubstituted aryl. In embodiments, R^(2A) is independently substitutedheteroaryl. In embodiments, R^(2A) is independently unsubstitutedcycloalkyl. In embodiments, R^(2A) is independently unsubstitutedheterocycloalkyl. In embodiments, R^(2A) is independently unsubstitutedaryl. In embodiments, R^(2A) is independently unsubstituted heteroaryl.

In embodiments, R^(2B) is independently hydrogen. In embodiments, R^(2B)is independently substituted or unsubstituted alkyl. In embodiments,R^(2B) is independently substituted or unsubstituted heteroalkyl. Inembodiments, R^(2B) is independently substituted or unsubstitutedcycloalkyl. In embodiments, R^(2B) is independently substituted orunsubstituted heterocycloalkyl. In embodiments, R^(2B) is independentlysubstituted or unsubstituted aryl. In embodiments, R^(2B) isindependently substituted or unsubstituted heteroaryl. In embodiments,R^(2B) is independently substituted alkyl. In embodiments, R^(2B) isindependently substituted heteroalkyl. In embodiments, R^(2B) isindependently substituted cycloalkyl. In embodiments, R^(2B) isindependently substituted heterocycloalkyl. In embodiments, R^(2B) isindependently substituted aryl. In embodiments, R^(2B) is independentlysubstituted heteroaryl. In embodiments, R^(2B) is independentlyunsubstituted alkyl. In embodiments, R^(2B) is independentlyunsubstituted heteroalkyl. In embodiments, R^(2B) is independentlyunsubstituted cycloalkyl. In embodiments, R^(2B) is independentlyunsubstituted heterocycloalkyl. In embodiments, R^(2B) is independentlyunsubstituted aryl. In embodiments, R^(2B) is independentlyunsubstituted heteroaryl.

In embodiments, R^(2C) is independently hydrogen. In embodiments, R^(2C)is independently substituted or unsubstituted alkyl. In embodiments,R^(2C) is independently substituted or unsubstituted heteroalkyl. Inembodiments, R^(2C) is independently substituted or unsubstitutedcycloalkyl. In embodiments, R^(2C) is independently substituted orunsubstituted heterocycloalkyl. In embodiments, R^(2C) is independentlysubstituted or unsubstituted aryl. In embodiments, R^(2C) isindependently substituted or unsubstituted heteroaryl. In embodiments,R^(2C) is independently substituted alkyl. In embodiments, R^(2C) isindependently substituted heteroalkyl. In embodiments, R^(2C) isindependently substituted cycloalkyl. In embodiments, R^(2C) isindependently substituted heterocycloalkyl. In embodiments, R^(2C) isindependently substituted aryl. In embodiments, R^(2C) is independentlysubstituted heteroaryl. In embodiments, R^(2C) is independentlyunsubstituted alkyl. In embodiments, R^(2C) is independentlyunsubstituted heteroalkyl. In embodiments, R^(2C) is independentlyunsubstituted cycloalkyl. In embodiments, R^(2C) is independentlyunsubstituted heterocycloalkyl. In embodiments, R^(2C) is independentlyunsubstituted aryl. In embodiments, R^(2C) is independentlyunsubstituted heteroaryl.

In embodiments, R^(2B) and R^(2C) combine to form a substituted orunsubstituted heterocycloalkyl. In embodiments, R^(2B) and R^(2C)combine to form a substituted heterocycloalkyl. In embodiments, R^(2B)and R^(2C) combine to form an unsubstituted heterocycloalkyl.

R⁶ and R⁷ substituents bonded to the same nitrogen atom may be joined toform a substituted or unsubstituted heterocycloalkyl. R⁶ and R⁷substituents bonded to the same nitrogen atom may be joined to form asubstituted or unsubstituted heteroaryl. R⁶ and R⁷ substituents bondedto the same nitrogen atom may be joined to form a substitutedheterocycloalkyl. R⁶ and R⁷ substituents bonded to the same nitrogenatom may be joined to form a substituted heteroaryl. R⁶ and R⁷substituents bonded to the same nitrogen atom may be joined to form anunsubstituted heterocycloalkyl. R⁶ and R⁷ substituents bonded to thesame nitrogen atom may be joined to form an unsubstituted heteroaryl. R⁶and R⁷ substituents bonded to the same nitrogen atom may be joined toform a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. R⁶and R⁷ substituents bonded to the same nitrogen atom may be joined toform a substituted or unsubstituted 5 to 6 membered heteroaryl. R⁶ andR⁷ substituents bonded to the same nitrogen atom may be joined to form asubstituted 3 to 8 membered heterocycloalkyl. R⁶ and R⁷ substituentsbonded to the same nitrogen atom may be joined to form a substituted 5to 6 membered heteroaryl. R⁶ and R⁷ substituents bonded to the samenitrogen atom may be joined to form an unsubstituted 3 to 8 memberedheterocycloalkyl. R⁶ and R⁷ substituents bonded to the same nitrogenatom may be joined to form an unsubstituted 5 to 6 membered heteroaryl.

R¹⁰ and R¹¹ substituents bonded to the same nitrogen atom may be joinedto form a substituted or unsubstituted heterocycloalkyl. R¹⁰ and R¹¹substituents bonded to the same nitrogen atom may be joined to form asubstituted or unsubstituted heteroaryl. R¹⁰ and R¹¹ substituents bondedto the same nitrogen atom may be joined to form a substitutedheterocycloalkyl. R¹⁰ and R¹¹ substituents bonded to the same nitrogenatom may be joined to form a substituted heteroaryl. R¹⁰ and R¹¹substituents bonded to the same nitrogen atom may be joined to form anunsubstituted heterocycloalkyl. R¹⁰ and R¹¹ substituents bonded to thesame nitrogen atom may be joined to form an unsubstituted heteroaryl.R¹⁰ and R¹¹ substituents bonded to the same nitrogen atom may be joinedto form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl.R¹⁰ and R¹¹ substituents bonded to the same nitrogen atom may be joinedto form a substituted or unsubstituted 5 to 6 membered heteroaryl. R¹⁰and R¹¹ substituents bonded to the same nitrogen atom may be joined toform a substituted 3 to 8 membered heterocycloalkyl. R¹⁰ and R¹¹substituents bonded to the same nitrogen atom may be joined to form asubstituted 5 to 6 membered heteroaryl. R¹⁰ and R¹¹ substituents bondedto the same nitrogen atom may be joined to form an unsubstituted 3 to 8membered heterocycloalkyl. R¹⁰ and R¹¹ substituents bonded to the samenitrogen atom may be joined to form an unsubstituted 5 to 6 memberedheteroaryl.

R¹⁴ and R¹⁵ substituents bonded to the same nitrogen atom may be joinedto form a substituted or unsubstituted heterocycloalkyl. R¹⁴ and R¹⁵substituents bonded to the same nitrogen atom may be joined to form asubstituted or unsubstituted heteroaryl. R¹⁴ and R¹⁵ substituents bondedto the same nitrogen atom may be joined to form a substitutedheterocycloalkyl. R¹⁴ and R¹⁵ substituents bonded to the same nitrogenatom may be joined to form a substituted heteroaryl. R¹⁴ and R¹⁵substituents bonded to the same nitrogen atom may be joined to form anunsubstituted heterocycloalkyl. R¹⁴ and R¹⁵ substituents bonded to thesame nitrogen atom may be joined to form an unsubstituted heteroaryl.R¹⁴ and R¹⁵ substituents bonded to the same nitrogen atom may be joinedto form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl.R¹⁴ and R¹⁵ substituents bonded to the same nitrogen atom may be joinedto form a substituted or unsubstituted 5 to 6 membered heteroaryl. R¹⁴and R¹⁵ substituents bonded to the same nitrogen atom may be joined toform a substituted 3 to 8 membered heterocycloalkyl. R¹⁴ and R¹⁵substituents bonded to the same nitrogen atom may be joined to form asubstituted 5 to 6 membered heteroaryl. R¹⁴ and R¹⁵ substituents bondedto the same nitrogen atom may be joined to form an unsubstituted 3 to 8membered heterocycloalkyl. R¹⁴ and R¹⁵ substituents bonded to the samenitrogen atom may be joined to form an unsubstituted 5 to 6 memberedheteroaryl.

R¹⁸ and R¹⁹ substituents bonded to the same nitrogen atom may be joinedto form a substituted or unsubstituted heterocycloalkyl. R¹⁸ and R¹⁹substituents bonded to the same nitrogen atom may be joined to form asubstituted or unsubstituted heteroaryl. R¹⁸ and R¹⁹ substituents bondedto the same nitrogen atom may be joined to form a substitutedheterocycloalkyl. R¹⁸ and R¹⁹ substituents bonded to the same nitrogenatom may be joined to form a substituted heteroaryl. R¹⁸ and R¹⁹substituents bonded to the same nitrogen atom may be joined to form anunsubstituted heterocycloalkyl. R¹⁸ and R¹⁹ substituents bonded to thesame nitrogen atom may be joined to form an unsubstituted heteroaryl.R¹⁸ and R¹⁹ substituents bonded to the same nitrogen atom may be joinedto form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl.R¹⁸ and R¹⁹ substituents bonded to the same nitrogen atom may be joinedto form a substituted or unsubstituted 5 to 6 membered heteroaryl. R¹⁸and R¹⁹ substituents bonded to the same nitrogen atom may be joined toform a substituted 3 to 8 membered heterocycloalkyl. R¹⁸ and R¹⁹substituents bonded to the same nitrogen atom may be joined to form asubstituted 5 to 6 membered heteroaryl. R¹⁸ and R¹⁹ substituents bondedto the same nitrogen atom may be joined to form an unsubstituted 3 to 8membered heterocycloalkyl. R¹⁸ and R¹⁹ substituents bonded to the samenitrogen atom may be joined to form an unsubstituted 5 to 6 memberedheteroaryl.

Each X³ is independently —F. Each X³ is independently —Cl. Each X³ isindependently —Br. Each X³ is independently —I.

Each X⁴ is independently —F. Each X⁴ is independently —Cl. Each X⁴ isindependently —Br. Each X⁴ is independently —I.

Each X⁵ is independently —F. Each X⁵ is independently —Cl. Each X⁵ isindependently —Br. Each X⁵ is independently —I.

Each X⁶ is independently —F. Each X⁶ is independently —Cl. Each X⁶ isindependently —Br. Each X⁶ is independently —I.

Each m3 is independently 1. Each m3 is independently 2. Each m4 isindependently 1. Each m4 is independently 2. Each m5 is independently 1.Each m5 is independently 2. Each m6 is independently 1. Each m6 isindependently 2.

Each n3 is independently 0. Each n3 is independently 1. Each n3 isindependently 2. Each n3 is independently 3. Each n4 is independently 0.Each n4 is independently 1. Each n4 is independently 2. Each n4 isindependently 3. Each n5 is independently 0. Each n5 is independently 1.Each n5 is independently 2. Each n5 is independently 3. Each n6 isindependently 0. Each n6 is independently 1. Each n6 is independently 2.Each n6 is independently 3.

Each v3 is independently 1. Each v3 is independently 2. Each v4 isindependently 1. Each v4 is independently 2. Each v5 is independently 1.Each v5 is independently 2. Each v6 is independently 1. Each v6 isindependently 2.

In embodiments, L¹ is independently a bond, R²⁹-substituted orunsubstituted alkylene, R²⁹-substituted or unsubstituted heteroalkylene,R²⁹-substituted or unsubstituted cycloalkylene, R²⁹-substituted orunsubstituted heterocycloalkylene, R²⁹-substituted or unsubstitutedarylene, or R²⁹-substituted or unsubstituted heteroarylene.

R²⁹ is independently oxo, halogen, —CX²⁹ ₃, —CHX²⁹ ₂, —CH₂X²⁹, —OCX²⁹ ₃,—OCHX²⁹ ₂, —OCH₂X²⁹, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R³⁰-substituted or unsubstituted alkyl,R³⁰-substituted or unsubstituted heteroalkyl, R³⁰-substituted orunsubstituted cycloalkyl, R³⁰-substituted or unsubstitutedheterocycloalkyl, R³⁰-substituted or unsubstituted aryl, orR³⁰-substituted or unsubstituted heteroaryl. X²⁹ is halogen. Inembodiments, X²⁹ is F.

R³⁰ is independently oxo, halogen, —CX³⁰ ₃, —CHX³⁰ ₂, —CH₂X³⁰, —OCX³⁰ ₃,—OCHX³⁰ ₂, —OCH₂X³⁰, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R³¹-substituted or unsubstituted alkyl,R³¹-substituted or unsubstituted heteroalkyl, R³¹-substituted orunsubstituted cycloalkyl, R³¹-substituted or unsubstitutedheterocycloalkyl, R³-substituted or unsubstituted aryl, orR³-substituted or unsubstituted heteroaryl. X³⁰ is halogen. Inembodiments, X³⁰ is F.

In embodiments, R¹ is independently hydrogen, —NR¹⁰R¹¹, —OR¹²,R³²-substituted or unsubstituted alkyl, R³²-substituted or unsubstitutedheteroalkyl, R³²-substituted or unsubstituted cycloalkyl,R³²-substituted or unsubstituted heterocycloalkyl, R³²-substituted orunsubstituted aryl, or R³²-substituted or unsubstituted heteroaryl.

R³² is independently oxo, halogen, —CX³² ₃, —CHX³² ₂, —CH₂X³², —OCX³² ₃,—OCHX³² ₂, —OCH₂X³², —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R³³-substituted or unsubstituted alkyl,R³³-substituted or unsubstituted heteroalkyl, R³³-substituted orunsubstituted cycloalkyl, R³³-substituted or unsubstitutedheterocycloalkyl, R³³-substituted or unsubstituted aryl, orR³³-substituted or unsubstituted heteroaryl. X³² is halogen. Inembodiments, X³² is F.

R³³ is independently oxo, halogen, —CX³³ ₃, —CHX³³ ₂, —CH₂X³³, —OCX³³ ₃,—OCHX³³ ₂, —OCH₂X³³, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R³⁴-substituted or unsubstituted alkyl,R³⁴-substituted or unsubstituted heteroalkyl, R³⁴-substituted orunsubstituted cycloalkyl, R³⁴-substituted or unsubstitutedheterocycloalkyl, R³⁴-substituted or unsubstituted aryl, orR³⁴-substituted or unsubstituted heteroaryl. X³³ is halogen. Inembodiments, X³³ is F.

In embodiments, R² is independently hydrogen, R³⁵-substituted orunsubstituted alkyl, R³⁵-substituted or unsubstituted heteroalkyl,R³⁵-substituted or unsubstituted cycloalkyl, R³⁵-substituted orunsubstituted heterocycloalkyl, R³⁵-substituted or unsubstituted aryl,or R³⁵-substituted or unsubstituted heteroaryl.

R³⁵ is independently oxo, halogen, —CX³⁵ ₃, —CHX³⁵ ₂, —CH₂X³⁵, —OCX³⁵ ₃,—OCHX³⁵ ₂, —OCH₂X³⁵, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R³⁶-substituted or unsubstituted alkyl,R³⁶-substituted or unsubstituted heteroalkyl, R³⁶-substituted orunsubstituted cycloalkyl, R³⁶-substituted or unsubstitutedheterocycloalkyl, R³⁶-substituted or unsubstituted aryl, orR³⁶-substituted or unsubstituted heteroaryl. X³⁵ is halogen. Inembodiments, X³⁵ is F.

R³⁶ is independently oxo, halogen, —CX³⁶ ₃, —CHX³⁶ ₂, —CH₂X³⁶, —OCX³⁶ ₃,—OCHX³⁶ ₂, —OCH₂X³⁶, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R³⁷-substituted or unsubstituted alkyl,R³⁷-substituted or unsubstituted heteroalkyl, R³⁷-substituted orunsubstituted cycloalkyl, R³⁷-substituted or unsubstitutedheterocycloalkyl, R³⁷-substituted or unsubstituted aryl, orR³⁷-substituted or unsubstituted heteroaryl. X³⁶ is halogen. Inembodiments, X³⁶ is F.

In embodiments, R³ is independently hydrogen, halogen, —CX³ ₃, —CHX³ ₂,—CH₂X³, —OCX³ ₃, —OCHX³ ₂, —OCH₂X³, —CN, —SO_(n3)R¹⁶, —SO_(v3)NR¹³R¹⁴,—NHC(O)NR¹³R¹⁴, —N(O)_(m3), —NR¹³R¹⁴, —C(O)R¹⁵, —C(O)—OR¹⁵,—C(O)NR¹³R¹⁴, —OR¹⁶, —NR¹³SO₂R¹⁶, —NR¹³C(O)R¹⁵, —NR¹³C(O)OR¹⁵, —NR¹³R¹⁵,R³⁸-substituted or unsubstituted alkyl, R³⁸-substituted or unsubstitutedheteroalkyl, R³⁸-substituted or unsubstituted cycloalkyl,R³⁸-substituted or unsubstituted heterocycloalkyl, R³⁸-substituted orunsubstituted aryl, or R³⁸-substituted or unsubstituted heteroaryl.

In embodiments, R⁴ is independently hydrogen, halogen, —CX⁴ ₃, —CHX⁴ ₂,—CH₂X⁴, —OCX⁴ ₃, —OCHX⁴ ₂, —OCH₂X⁴, —CN, —SO_(n4)R²⁰, —SO_(v4)NR¹⁷R¹⁸,—NHC(O)NR¹⁷R¹⁸, —N(O)_(m4), —NR¹⁷R¹⁸, —C(O)R¹⁹, —C(O)—OR¹⁹,—C(O)NR¹⁷R¹⁸, —OR²⁰, —NR¹⁷SO₂R²⁰, —NR¹⁷C(O)R¹⁹, —NR¹⁷C(O)OR¹⁹,—NR¹⁷OR¹⁹, R³⁹-substituted or unsubstituted alkyl, R³⁹-substituted orunsubstituted heteroalkyl, R³⁹-substituted or unsubstituted cycloalkyl,R³⁹-substituted or unsubstituted heterocycloalkyl, R³⁹-substituted orunsubstituted aryl, or R³⁹-substituted or unsubstituted heteroaryl.

In embodiments, R⁵ is independently hydrogen, halogen, —CX⁵ ₃, —CHX⁵ ₂,—CH₂X⁵, —OCX⁵ ₃, —OCHX⁵ ₂, —OCH₂X⁵, —CN, —SO_(n5)R²⁴, —SO_(v5)NR²¹R²²,—NHC(O)NR²¹R²², —N(O)_(m5), —NR²¹R²², —C(O)R²³, —C(O)—OR²³,—C(O)NR²¹R²², —OR²⁴, —NR²¹SO₂R²⁴, —NR²¹C(O)R²³, —NR²¹C(O)OR²³,—NR²¹OR²³, R⁴⁰-substituted or unsubstituted alkyl, R⁴⁰-substituted orunsubstituted heteroalkyl, R⁴⁰-substituted or unsubstituted cycloalkyl,R⁴⁰-substituted or unsubstituted heterocycloalkyl, R⁴⁰-substituted orunsubstituted aryl, or R⁴⁰-substituted or unsubstituted heteroaryl.

In embodiments, R⁶ is independently hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂,—CH₂X⁶, —OCX⁶ ₃, —OCHX⁶ ₂, —OCH₂X⁶, —CN, —SO_(n6)R²⁸, —SO_(v6)NR²⁵R²⁶,—NHC(O)NR²⁵R²⁶, —N(O)_(m6), —NR²⁵R²⁶, —C(O)R²⁷, —C(O)—OR²⁷,—C(O)NR²⁵R²⁶, —OR²⁸, —NR²⁵SO₂R²⁸, —NR²⁵C(O)R²⁷, —NR²⁵C(O)OR²⁷,—NR²⁵OR²⁷, R⁴¹-substituted or unsubstituted alkyl, R⁴¹-substituted orunsubstituted heteroalkyl, R⁴¹-substituted or unsubstituted cycloalkyl,R⁴¹-substituted or unsubstituted heterocycloalkyl, R⁴¹-substituted orunsubstituted aryl, or R⁴¹-substituted or unsubstituted heteroaryl.

In embodiments, each R⁷ is independently hydrogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, R⁴²-substituted or unsubstituted alkyl,R⁴²-substituted or unsubstituted heteroalkyl, R⁴²-substituted orunsubstituted cycloalkyl, R⁴²-substituted or unsubstitutedheterocycloalkyl, R⁴²-substituted or unsubstituted aryl, orR⁴²-substituted or unsubstituted heteroaryl. Each X is independently —F,—Cl, —Br, or —I. In embodiments, X is —F.

R⁴² is independently oxo, halogen, —CX⁴² ₃, —CHX⁴² ₂, —CH₂X⁴², —OCHX⁴²₂, —OCX⁴² ₃, —OCH₂X⁴², —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁴³-substituted or unsubstituted alkyl,R⁴³-substituted or unsubstituted heteroalkyl, R⁴³-substituted orunsubstituted cycloalkyl, R⁴³-substituted or unsubstitutedheterocycloalkyl, R⁴³-substituted or unsubstituted aryl, orR⁴³-substituted or unsubstituted heteroaryl. X⁴² is halogen. Inembodiments, X⁴² is F.

R⁴³ is independently oxo, halogen, —CX⁴³ ₃, —CHX⁴³ ₂, —CH₂X⁴³, —OCHX⁴³₂, —OCX⁴³ ₃, —OCH₂X⁴³, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁴⁴-substituted or unsubstituted alkyl,R⁴⁴-substituted or unsubstituted heteroalkyl, R⁴⁴-substituted orunsubstituted cycloalkyl, R⁴⁴-substituted or unsubstitutedheterocycloalkyl, R⁴⁴-substituted or unsubstituted aryl, orR⁴⁴-substituted or unsubstituted heteroaryl. X⁴³ is halogen. Inembodiments, X⁴³ is F.

In embodiments, each R⁸ is independently hydrogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, R⁴⁵-substituted or unsubstituted alkyl,R⁴⁵-substituted or unsubstituted heteroalkyl, R⁴⁵-substituted orunsubstituted cycloalkyl, R⁴⁵-substituted or unsubstitutedheterocycloalkyl, R⁴⁵-substituted or unsubstituted aryl, orR⁴⁵-substituted or unsubstituted heteroaryl. Each X is independently —F,—Cl, —Br, or —I. In embodiments, X is —F.

R⁴⁵ is independently oxo, halogen, —CX⁴⁵ ₃, —CHX⁴⁵ ₂, —CH₂X⁴⁵, —OCHX⁴⁵₂, —OCX⁴⁵ ₃, —OCH₂X⁴⁵, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁴⁶-substituted or unsubstituted alkyl,R⁴⁶-substituted or unsubstituted heteroalkyl, R⁴⁶-substituted orunsubstituted cycloalkyl, R⁴⁶-substituted or unsubstitutedheterocycloalkyl, R⁴⁶-substituted or unsubstituted aryl, orR⁴⁶-substituted or unsubstituted heteroaryl. X⁴⁵ is halogen. Inembodiments, X⁴⁵ is F.

R⁴⁶ is independently oxo, halogen, —CX⁴⁶ ₃, —CHX⁴⁶ ₂, —CH₂X⁴⁶, —OCHX⁴⁶₂, —OCX⁴⁶ ₃, —OCH₂X⁴⁶, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁴⁷-substituted or unsubstituted alkyl,R⁴⁷-substituted or unsubstituted heteroalkyl, R⁴⁷-substituted orunsubstituted cycloalkyl, R⁴⁷-substituted or unsubstitutedheterocycloalkyl, R⁴⁷-substituted or unsubstituted aryl, orR⁴⁷-substituted or unsubstituted heteroaryl. X⁴⁶ is halogen. Inembodiments, X⁴⁶ is F.

In embodiments, each R⁹ is independently hydrogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, R⁴⁸-substituted or unsubstituted alkyl,R⁴⁸-substituted or unsubstituted heteroalkyl, R⁴⁸-substituted orunsubstituted cycloalkyl, R⁴⁸-substituted or unsubstitutedheterocycloalkyl, R⁴⁸-substituted or unsubstituted aryl, orR⁴⁸-substituted or unsubstituted heteroaryl. Each X is independently —F,—Cl, —Br, or —I. In embodiments, X is —F.

R⁴⁸ is independently oxo, halogen, —CX⁴⁸ ₃, —CHX⁴⁸ ₂, —CH₂X⁴⁸, —OCHX⁴⁸₂, —OCX⁴⁸ ₃, —OCH₂X⁴⁸, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁴⁹-substituted or unsubstituted alkyl,R⁴⁹-substituted or unsubstituted heteroalkyl, R⁴⁹-substituted orunsubstituted cycloalkyl, R⁴⁹-substituted or unsubstitutedheterocycloalkyl, R⁴⁹-substituted or unsubstituted aryl, orR⁴⁹-substituted or unsubstituted heteroaryl. X⁴⁸ is halogen. Inembodiments, X⁴⁸ is F.

R⁴⁹ is independently oxo, halogen, —CX⁴⁹ ₃, —CHX⁴⁹ ₂, —CH₂X⁴⁹, —OCHX⁴⁹₂, —OCX⁴⁹ ₃, —OCH₂X⁴⁹, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁵⁰-substituted or unsubstituted alkyl,R⁵⁰-substituted or unsubstituted heteroalkyl, R⁵⁰-substituted orunsubstituted cycloalkyl, R⁵⁰-substituted or unsubstitutedheterocycloalkyl, R⁵⁰-substituted or unsubstituted aryl, orR⁵⁰-substituted or unsubstituted heteroaryl. X⁴⁹ is halogen. Inembodiments, X⁴⁹ is F.

In embodiments, each R¹⁰ is independently hydrogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, R⁵¹-substituted or unsubstituted alkyl,R⁵¹-substituted or unsubstituted heteroalkyl, R⁵¹-substituted orunsubstituted cycloalkyl, R⁵¹-substituted or unsubstitutedheterocycloalkyl, R⁵¹-substituted or unsubstituted aryl, orR⁵¹-substituted or unsubstituted heteroaryl. Each X is independently —F,—Cl, —Br, or —I. In embodiments, X is —F.

R⁵¹ is independently oxo, halogen, —CX⁵¹ ₃, —CHX⁵¹ ₂, —CH₂X⁵¹, —OCHX⁵¹₂, —OCX⁵¹ ₃, —OCH₂X⁵¹, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁵²-substituted or unsubstituted alkyl,R⁵²-substituted or unsubstituted heteroalkyl, R⁵²-substituted orunsubstituted cycloalkyl, R⁵²-substituted or unsubstitutedheterocycloalkyl, R⁵²-substituted or unsubstituted aryl, orR⁵²-substituted or unsubstituted heteroaryl. X⁵¹ is halogen. Inembodiments, X⁵¹ is F.

R⁵² is independently oxo, halogen, —CX⁵² ₃, —CHX⁵² ₂, —CH₂X⁵², —OCHX⁵²₂, —OCX⁵² ₃, —OCH₂X⁵², —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁵³-substituted or unsubstituted alkyl,R⁵³-substituted or unsubstituted heteroalkyl, R⁵³-substituted orunsubstituted cycloalkyl, R⁵³-substituted or unsubstitutedheterocycloalkyl, R⁵³-substituted or unsubstituted aryl, orR⁵³-substituted or unsubstituted heteroaryl. X⁵² is halogen. Inembodiments, X⁵² is F.

In embodiments, each R¹¹ is independently hydrogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, R⁵⁴-substituted or unsubstituted alkyl,R⁵⁴-substituted or unsubstituted heteroalkyl, R⁵⁴-substituted orunsubstituted cycloalkyl, R⁵⁴-substituted or unsubstitutedheterocycloalkyl, R⁵⁴-substituted or unsubstituted aryl, orR⁵⁴-substituted or unsubstituted heteroaryl. Each X is independently —F,—Cl, —Br, or —I. In embodiments, X is —F.

R⁵⁴ is independently oxo, halogen, —CX⁵⁴ ₃, —CHX⁵⁴ ₂, —CH₂X⁵⁴, —OCHX⁵⁴₂, —OCX⁵⁴ ₃, —OCH₂X⁵⁴, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁵⁵-substituted or unsubstituted alkyl,R⁵⁵-substituted or unsubstituted heteroalkyl, R⁵⁵-substituted orunsubstituted cycloalkyl, R⁵⁵-substituted or unsubstitutedheterocycloalkyl, R⁵⁵-substituted or unsubstituted aryl, orR⁵⁵-substituted or unsubstituted heteroaryl. X⁵⁴ is halogen. Inembodiments, X⁵⁴ is F.

R⁵⁵ is independently oxo, halogen, —CX⁵⁵ ₃, —CHX⁵⁵ ₂, —CH₂X⁵⁵, —OCHX⁵⁵₂, —OCX⁵⁵ ₃, —OCH₂X⁵⁵, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁵⁶-substituted or unsubstituted alkyl,R⁵⁶-substituted or unsubstituted heteroalkyl, R⁵⁶-substituted orunsubstituted cycloalkyl, R⁵⁶-substituted or unsubstitutedheterocycloalkyl, R⁵⁶-substituted or unsubstituted aryl, orR⁵⁶-substituted or unsubstituted heteroaryl. X⁵⁵ is halogen. Inembodiments, X⁵⁵ is F.

In embodiments, each R¹² is independently hydrogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, R⁵⁷-substituted or unsubstituted alkyl,R⁵⁷-substituted or unsubstituted heteroalkyl, R⁵⁷-substituted orunsubstituted cycloalkyl, R⁵⁷-substituted or unsubstitutedheterocycloalkyl, R⁵⁷-substituted or unsubstituted aryl, orR⁵⁷-substituted or unsubstituted heteroaryl. Each X is independently —F,—Cl, —Br, or —I. In embodiments, X is —F.

R⁵⁷ is independently oxo, halogen, —CX⁵⁷ ₃, —CHX⁵⁷ ₂, —CH₂X⁵⁷, —OCHX⁵⁷₂, —OCX⁵⁷ ₃, —OCH₂X⁵⁷, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁵⁸-substituted or unsubstituted alkyl,R⁵⁸-substituted or unsubstituted heteroalkyl, R⁵⁸-substituted orunsubstituted cycloalkyl, R⁵⁸-substituted or unsubstitutedheterocycloalkyl, R⁵⁸-substituted or unsubstituted aryl, orR⁵⁸-substituted or unsubstituted heteroaryl. X⁵⁷ is halogen. Inembodiments, X⁵⁷ is F.

R⁵⁸ is independently oxo, halogen, —CX⁵⁸ ₃, —CHX⁵⁸ ₂, —CH₂X⁵⁸, —OCHX⁵⁸₂, —OCX⁵⁸ ₃, —OCH₂X⁵⁸, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁵⁹-substituted or unsubstituted alkyl,R⁵⁹-substituted or unsubstituted heteroalkyl, R⁵⁹-substituted orunsubstituted cycloalkyl, R⁵⁹-substituted or unsubstitutedheterocycloalkyl, R⁵⁹-substituted or unsubstituted aryl, orR⁵⁹-substituted or unsubstituted heteroaryl. X⁵⁸ is halogen. Inembodiments, X⁵⁸ is F.

In embodiments, each R¹³ is independently hydrogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, R⁶⁰-substituted or unsubstituted alkyl,R⁶⁰-substituted or unsubstituted heteroalkyl, R⁶⁰-substituted orunsubstituted cycloalkyl, R⁶⁰-substituted or unsubstitutedheterocycloalkyl, R⁶⁰-substituted or unsubstituted aryl, orR⁶⁰-substituted or unsubstituted heteroaryl. Each X is independently —F,—Cl, —Br, or —I. In embodiments, X is —F.

R⁶⁰ is independently oxo, halogen, —CX⁶⁰ ₃, —CHX⁶⁰ ₂, —CH₂X⁶⁰, —OCHX⁶⁰₂, —OCX⁶⁰ ₃, —OCH₂X⁶⁰, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁶¹-substituted or unsubstituted alkyl,R⁶¹-substituted or unsubstituted heteroalkyl, R⁶¹-substituted orunsubstituted cycloalkyl, R⁶¹-substituted or unsubstitutedheterocycloalkyl, R⁶¹-substituted or unsubstituted aryl, orR⁶¹-substituted or unsubstituted heteroaryl. X⁶⁰ is halogen. Inembodiments, X⁶⁰ is F.

R⁶¹ is independently oxo, halogen, —CX⁶¹ ₃, —CHX⁶¹ ₂, —CH₂X⁶¹, —OCHX⁶¹₂, —OCX⁶¹ ₃, —OCH₂X⁶¹, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁶²-substituted or unsubstituted alkyl,R⁶²-substituted or unsubstituted heteroalkyl, R⁶²-substituted orunsubstituted cycloalkyl, R⁶²-substituted or unsubstitutedheterocycloalkyl, R⁶²-substituted or unsubstituted aryl, orR⁶²-substituted or unsubstituted heteroaryl. X⁶¹ is halogen. Inembodiments, X⁶¹ is F.

In embodiments, each R¹⁴ is independently hydrogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, R⁶³-substituted or unsubstituted alkyl,R⁶³-substituted or unsubstituted heteroalkyl, R⁶³-substituted orunsubstituted cycloalkyl, R⁶³-substituted or unsubstitutedheterocycloalkyl, R⁶³-substituted or unsubstituted aryl, orR⁶³-substituted or unsubstituted heteroaryl. Each X is independently —F,—Cl, —Br, or —I. In embodiments, X is —F.

R⁶³ is independently oxo, halogen, —CX⁶³ ₃, —CHX⁶³ ₂, —CH₂X⁶³, —OCHX⁶³₂, —OCX⁶³ ₃, —OCH₂X⁶³, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁶⁴-substituted or unsubstituted alkyl,R⁶⁴-substituted or unsubstituted heteroalkyl, R⁶⁴-substituted orunsubstituted cycloalkyl, R⁶⁴-substituted or unsubstitutedheterocycloalkyl, R⁶⁴-substituted or unsubstituted aryl, orR⁶⁴-substituted or unsubstituted heteroaryl. X⁶³ is halogen. Inembodiments, X⁶³ is F.

R⁶⁴ is independently oxo, halogen, —CX⁶⁴ ₃, —CHX⁶⁴ ₂, —CH₂X⁶⁴, —OCHX⁶⁴₂, —OCX⁶⁴ ₃, —OCH₂X⁶⁴, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁶⁵-substituted or unsubstituted alkyl,R⁶⁵-substituted or unsubstituted heteroalkyl, R⁶⁵-substituted orunsubstituted cycloalkyl, R⁶⁵-substituted or unsubstitutedheterocycloalkyl, R⁶⁵-substituted or unsubstituted aryl, orR⁶⁵-substituted or unsubstituted heteroaryl. X⁶⁴ is halogen. Inembodiments, X⁶⁴ is F.

In embodiments, each R¹⁵ is independently hydrogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, R⁶⁶-substituted or unsubstituted alkyl,R⁶⁶-substituted or unsubstituted heteroalkyl, R⁶⁶-substituted orunsubstituted cycloalkyl, R⁶⁶-substituted or unsubstitutedheterocycloalkyl, R⁶⁶-substituted or unsubstituted aryl, orR⁶⁶-substituted or unsubstituted heteroaryl. Each X is independently —F,—Cl, —Br, or —I. In embodiments, X is —F.

R⁶⁶ is independently oxo, halogen, —CX⁶⁶ ₃, —CHX⁶⁶ ₂, —CH₂X⁶⁶, —OCHX⁶⁶₂, —OCX⁶⁶ ₃, —OCH₂X⁶⁶, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁶⁷-substituted or unsubstituted alkyl,R⁶⁷-substituted or unsubstituted heteroalkyl, R⁶⁷-substituted orunsubstituted cycloalkyl, R⁶⁷-substituted or unsubstitutedheterocycloalkyl, R⁶⁷-substituted or unsubstituted aryl, orR⁶⁷-substituted or unsubstituted heteroaryl. X⁶⁶ is halogen. Inembodiments, X⁶⁶ is F.

R⁶⁷ is independently oxo, halogen, —CX⁶⁷ ₃, —CHX⁶⁷ ₂, —CH₂X⁶⁷, —OCHX⁶⁷₂, —OCX⁶⁷ ₃, —OCH₂X⁶⁷, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁶⁸-substituted or unsubstituted alkyl,R⁶⁸-substituted or unsubstituted heteroalkyl, R⁶⁸-substituted orunsubstituted cycloalkyl, R⁶⁸-substituted or unsubstitutedheterocycloalkyl, R⁶⁸-substituted or unsubstituted aryl, orR⁶⁸-substituted or unsubstituted heteroaryl. X⁶⁷ is halogen. Inembodiments, X⁶⁷ is F.

In embodiments, each R¹⁶ is independently hydrogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, R⁶⁹-substituted or unsubstituted alkyl,R⁶⁹-substituted or unsubstituted heteroalkyl, R⁶⁹-substituted orunsubstituted cycloalkyl, R⁶⁹-substituted or unsubstitutedheterocycloalkyl, R⁶⁹-substituted or unsubstituted aryl, orR⁶⁹-substituted or unsubstituted heteroaryl. Each X is independently —F,—Cl, —Br, or —I. In embodiments, X is —F.

R⁶⁹ is independently oxo, halogen, —CX⁶⁹ ₃, —CHX⁶⁹ ₂, —CH₂X⁶⁹, —OCHX⁶⁹₂, —OCX⁶⁹ ₃, —OCH₂X⁶⁹, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁷⁰-substituted or unsubstituted alkyl,R⁷⁰-substituted or unsubstituted heteroalkyl, R⁷⁰-substituted orunsubstituted cycloalkyl, R⁷⁰-substituted or unsubstitutedheterocycloalkyl, R⁷⁰-substituted or unsubstituted aryl, orR⁷⁰-substituted or unsubstituted heteroaryl. X⁶⁹ is halogen. Inembodiments, X⁶⁹ is F.

R⁷⁰ is independently oxo, halogen, —CX⁷⁰ ₃, —CHX⁷⁰ ₂, —CH₂X⁷⁰, —OCHX⁷⁰₂, —OCX⁷⁰ ₃, —OCH₂X⁷⁰, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁷¹-substituted or unsubstituted alkyl,R⁷¹-substituted or unsubstituted heteroalkyl, R⁷¹-substituted orunsubstituted cycloalkyl, R⁷¹-substituted or unsubstitutedheterocycloalkyl, R⁷¹-substituted or unsubstituted aryl, orR⁷¹-substituted or unsubstituted heteroaryl. X⁷⁰ is halogen. Inembodiments, X⁷⁰ is F.

In embodiments, each R¹⁷ is independently hydrogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, R⁷²-substituted or unsubstituted alkyl,R⁷²-substituted or unsubstituted heteroalkyl, R⁷²-substituted orunsubstituted cycloalkyl, R⁷²-substituted or unsubstitutedheterocycloalkyl, R⁷²-substituted or unsubstituted aryl, orR⁷²-substituted or unsubstituted heteroaryl. Each X is independently —F,—Cl, —Br, or —I. In embodiments, X is —F.

R⁷² is independently oxo, halogen, —CX⁷² ₃, —CHX⁷² ₂, —CH₂X⁷², —OCHX⁷²₂, —OCX⁷² ₃, —OCH₂X⁷², —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁷³-substituted or unsubstituted alkyl,R⁷³-substituted or unsubstituted heteroalkyl, R⁷³-substituted orunsubstituted cycloalkyl, R⁷³-substituted or unsubstitutedheterocycloalkyl, R⁷³-substituted or unsubstituted aryl, orR⁷³-substituted or unsubstituted heteroaryl. X⁷² is halogen. Inembodiments, X⁷² is F.

R⁷³ is independently oxo, halogen, —CX⁷³ ₃, —CHX⁷³ ₂, —CH₂X⁷³, —OCHX⁷³₂, —OCX⁷³ ₃, —OCH₂X⁷³, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁷⁴-substituted or unsubstituted alkyl,R⁷⁴-substituted or unsubstituted heteroalkyl, R⁷⁴-substituted orunsubstituted cycloalkyl, R⁷⁴-substituted or unsubstitutedheterocycloalkyl, R⁷⁴-substituted or unsubstituted aryl, orR⁷⁴-substituted or unsubstituted heteroaryl. X⁷³ is halogen. Inembodiments, X⁷³ is F.

In embodiments, each R¹⁸ is independently hydrogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, R⁷⁵-substituted or unsubstituted alkyl,R⁷⁵-substituted or unsubstituted heteroalkyl, R⁷⁵-substituted orunsubstituted cycloalkyl, R⁷⁵-substituted or unsubstitutedheterocycloalkyl, R⁷⁵-substituted or unsubstituted aryl, orR⁷⁵-substituted or unsubstituted heteroaryl. Each X is independently —F,—Cl, —Br, or —I. In embodiments, X is —F.

R⁷⁵ is independently oxo, halogen, —CX⁷⁵ ₃, —CHX⁷⁵ ₂, —CH₂X⁷⁵, —OCHX⁷⁵₂, —OCX⁷⁵ ₃, —OCH₂X⁷⁵, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁷⁶-substituted or unsubstituted alkyl,R⁷⁶-substituted or unsubstituted heteroalkyl, R⁷⁶-substituted orunsubstituted cycloalkyl, R⁷⁶-substituted or unsubstitutedheterocycloalkyl, R⁷⁶-substituted or unsubstituted aryl, orR⁷⁶-substituted or unsubstituted heteroaryl. X⁷⁵ is halogen. Inembodiments, X⁷⁵ is F.

R⁷⁶ is independently oxo, halogen, —CX⁷⁶ ₃, —CHX⁷⁶ ₂, —CH₂X⁷⁶, —OCHX⁷⁶₂, —OCX⁷⁶ ₃, —OCH₂X⁷⁶, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁷⁷-substituted or unsubstituted alkyl,R⁷⁷-substituted or unsubstituted heteroalkyl, R⁷⁷-substituted orunsubstituted cycloalkyl, R⁷⁷-substituted or unsubstitutedheterocycloalkyl, R⁷⁷-substituted or unsubstituted aryl, orR⁷⁷-substituted or unsubstituted heteroaryl. X⁷⁶ is halogen. Inembodiments, X⁷⁶ is F.

In embodiments, each R¹⁹ is independently hydrogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, R⁷⁸-substituted or unsubstituted alkyl,R⁷⁸-substituted or unsubstituted heteroalkyl, R⁷⁸-substituted orunsubstituted cycloalkyl, R⁷⁸-substituted or unsubstitutedheterocycloalkyl, R⁷⁸-substituted or unsubstituted aryl, orR⁷⁸-substituted or unsubstituted heteroaryl. Each X is independently —F,—Cl, —Br, or —I. In embodiments, X is —F.

R⁷⁸ is independently oxo, halogen, —CX⁷⁸ ₃, —CHX⁷⁸ ₂, —CH₂X⁷⁸, —OCHX⁷⁸₂, —OCX⁷⁸ ₃, —OCH₂X⁷⁸, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁷⁹-substituted or unsubstituted alkyl,R⁷⁹-substituted or unsubstituted heteroalkyl, R⁷⁹-substituted orunsubstituted cycloalkyl, R⁷⁹-substituted or unsubstitutedheterocycloalkyl, R⁷⁹-substituted or unsubstituted aryl, orR⁷⁹-substituted or unsubstituted heteroaryl. X⁷⁸ is halogen. Inembodiments, X⁷⁸ is F.

R⁷⁹ is independently oxo, halogen, —CX⁷⁹ ₃, —CHX⁷⁹ ₂, —CH₂X⁷⁹, —OCHX⁷⁹₂, —OCX⁷⁹ ₃, —OCH₂X⁷⁹, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁸⁰-substituted or unsubstituted alkyl,R⁸⁰-substituted or unsubstituted heteroalkyl, R⁸⁰-substituted orunsubstituted cycloalkyl, R⁸⁰-substituted or unsubstitutedheterocycloalkyl, R⁸⁰-substituted or unsubstituted aryl, orR⁸⁰-substituted or unsubstituted heteroaryl. X⁷⁹ is halogen. Inembodiments, X⁷⁹ is F.

In embodiments, each R²⁰ is independently hydrogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, R⁸¹-substituted or unsubstituted alkyl,R⁸¹-substituted or unsubstituted heteroalkyl, R⁸¹-substituted orunsubstituted cycloalkyl, R⁸¹-substituted or unsubstitutedheterocycloalkyl, R⁸¹-substituted or unsubstituted aryl, orR⁸¹-substituted or unsubstituted heteroaryl. Each X is independently —F,—Cl, —Br, or —I. In embodiments, X is —F.

R⁸¹ is independently oxo, halogen, —CX⁸¹ ₃, —CHX⁸¹ ₂, —CH₂X⁸¹, —OCHX¹²,—OCX⁸¹ ₃, —OCH₂X⁸¹, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁸²-substituted or unsubstituted alkyl,R⁸²-substituted or unsubstituted heteroalkyl, R⁸²-substituted orunsubstituted cycloalkyl, R⁸²-substituted or unsubstitutedheterocycloalkyl, R⁸²-substituted or unsubstituted aryl, orR⁸²-substituted or unsubstituted heteroaryl. X⁸¹ is halogen. Inembodiments, X⁸¹ is F.

R⁸² is independently oxo, halogen, —CX⁸² ₃, —CHX⁸² ₂, —CH₂X⁸², —OCHX⁸²₂, —OCX⁸² ₃, —OCH₂X⁸², —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁸³-substituted or unsubstituted alkyl,R⁸³-substituted or unsubstituted heteroalkyl, R⁸³-substituted orunsubstituted cycloalkyl, R⁸³-substituted or unsubstitutedheterocycloalkyl, R⁸³-substituted or unsubstituted aryl, orR⁸³-substituted or unsubstituted heteroaryl. X⁸² is halogen. Inembodiments, X⁸² is F.

In embodiments, each R²¹ is independently hydrogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, R⁸⁴-substituted or unsubstituted alkyl,R⁸⁴-substituted or unsubstituted heteroalkyl, R⁸⁴-substituted orunsubstituted cycloalkyl, R⁸⁴-substituted or unsubstitutedheterocycloalkyl, R⁸⁴-substituted or unsubstituted aryl, orR⁸⁴-substituted or unsubstituted heteroaryl. Each X is independently —F,—Cl, —Br, or —I. In embodiments, X is —F.

R⁸⁴ is independently oxo, halogen, —CX⁸⁴ ₃, —CHX⁸⁴ ₂, —CH₂X⁸⁴, —OCHX⁸⁴₂, —OCX⁸⁴ ₃, —OCH₂X⁸⁴, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁸⁵-substituted or unsubstituted alkyl,R⁸⁵-substituted or unsubstituted heteroalkyl, R⁸⁵-substituted orunsubstituted cycloalkyl, R⁸⁵-substituted or unsubstitutedheterocycloalkyl, R⁸⁵-substituted or unsubstituted aryl, orR⁸⁵-substituted or unsubstituted heteroaryl. X⁸⁴ is halogen. Inembodiments, X⁸⁴ is F.

R⁸⁵ is independently oxo, halogen, —CX⁸⁵ ₃, —CHX⁸⁵ ₂, —CH₂X⁸⁵, —OCHX⁸⁵₂, —OCX⁸⁵ ₃, —OCH₂X⁸⁵, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁸⁶-substituted or unsubstituted alkyl,R⁸⁶-substituted or unsubstituted heteroalkyl, R⁸⁶-substituted orunsubstituted cycloalkyl, R⁸⁶-substituted or unsubstitutedheterocycloalkyl, R⁸⁶-substituted or unsubstituted aryl, orR⁸⁶-substituted or unsubstituted heteroaryl. X⁸⁵ is halogen. Inembodiments, X⁸⁵ is F.

In embodiments, each R²² is independently hydrogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, R⁸⁷-substituted or unsubstituted alkyl,R⁸⁷-substituted or unsubstituted heteroalkyl, R⁸⁷-substituted orunsubstituted cycloalkyl, R⁸⁷-substituted or unsubstitutedheterocycloalkyl, R⁸⁷-substituted or unsubstituted aryl, orR⁸⁷-substituted or unsubstituted heteroaryl. Each X is independently —F,—Cl, —Br, or —I. In embodiments, X is —F.

R⁸⁷ is independently oxo, halogen, —CX⁸⁷ ₃, —CHX⁸⁷ ₂, —CH₂X⁸⁷, —OCHX⁸⁷₂, —OCX⁸⁷ ₃, —OCH₂X⁸⁷, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁸⁸-substituted or unsubstituted alkyl,R⁸⁸-substituted or unsubstituted heteroalkyl, R⁸⁸-substituted orunsubstituted cycloalkyl, R⁸⁸-substituted or unsubstitutedheterocycloalkyl, R⁸⁸-substituted or unsubstituted aryl, orR⁸⁸-substituted or unsubstituted heteroaryl. X⁸⁷ is halogen. Inembodiments, X⁸⁷ is F.

R⁸⁸ is independently oxo, halogen, —CX⁸⁸ ₃, —CHX⁸⁸ ₂, —CH₂X⁸⁸, —OCHX⁸⁸₂, —OCX⁸⁸ ₃, —OCH₂X⁸⁸, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁸⁹-substituted or unsubstituted alkyl,R⁸⁹-substituted or unsubstituted heteroalkyl, R⁸⁹-substituted orunsubstituted cycloalkyl, R⁸⁹-substituted or unsubstitutedheterocycloalkyl, R⁸⁹-substituted or unsubstituted aryl, orR⁸⁹-substituted or unsubstituted heteroaryl. X⁸⁸ is halogen. Inembodiments, X⁸⁸ is F.

In embodiments, each R²³ is independently hydrogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, R⁹⁰-substituted or unsubstituted alkyl,R⁹⁰-substituted or unsubstituted heteroalkyl, R⁹⁰-substituted orunsubstituted cycloalkyl, R⁹⁰-substituted or unsubstitutedheterocycloalkyl, R⁹⁰-substituted or unsubstituted aryl, orR⁹⁰-substituted or unsubstituted heteroaryl. Each X is independently —F,—Cl, —Br, or —I. In embodiments, X is —F.

R⁹⁰ is independently oxo, halogen, —CX⁹⁰ ₃, —CHX⁹⁰ ₂, —CH₂X⁹⁰, —OCHX⁹⁰₂, —OCX⁹⁰ ₃, —OCH₂X⁹⁰, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁹¹-substituted or unsubstituted alkyl,R⁹¹-substituted or unsubstituted heteroalkyl, R⁹¹-substituted orunsubstituted cycloalkyl, R⁹¹-substituted or unsubstitutedheterocycloalkyl, R⁹¹-substituted or unsubstituted aryl, orR⁹¹-substituted or unsubstituted heteroaryl. X⁹⁰ is halogen. Inembodiments, X⁹⁰ is F.

R⁹¹ is independently oxo, halogen, —CX⁹¹ ₃, —CHX⁹¹ ₂, —CH₂X⁹¹, —OCHX⁹¹₂, —OCX⁹¹ ₃, —OCH₂X⁹¹, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁹²-substituted or unsubstituted alkyl,R⁹²-substituted or unsubstituted heteroalkyl, R⁹²-substituted orunsubstituted cycloalkyl, R⁹²-substituted or unsubstitutedheterocycloalkyl, R⁹²-substituted or unsubstituted aryl, orR⁹²-substituted or unsubstituted heteroaryl. X⁹¹ is halogen. Inembodiments, X⁹¹ is F.

In embodiments, each R²⁴ is independently hydrogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, R⁹³-substituted or unsubstituted alkyl,R⁹³-substituted or unsubstituted heteroalkyl, R⁹³-substituted orunsubstituted cycloalkyl, R⁹³-substituted or unsubstitutedheterocycloalkyl, R⁹³-substituted or unsubstituted aryl, orR⁹³-substituted or unsubstituted heteroaryl. Each X is independently —F,—Cl, —Br, or —I. In embodiments, X is —F.

R⁹³ is independently oxo, halogen, —CX⁹³ ₃, —CHX⁹³ ₂, —CH₂X⁹³, —OCHX⁹³₂, —OCX⁹³ ₃, —OCH₂X⁹³, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁹⁴-substituted or unsubstituted alkyl,R⁹⁴-substituted or unsubstituted heteroalkyl, R⁹⁴-substituted orunsubstituted cycloalkyl, R⁹⁴-substituted or unsubstitutedheterocycloalkyl, R⁹⁴-substituted or unsubstituted aryl, orR⁹⁴-substituted or unsubstituted heteroaryl. X⁹³ is halogen. Inembodiments, X⁹³ is F.

R⁹⁴ is independently oxo, halogen, —CX⁹⁴ ₃, —CHX⁹⁴ ₂, —CH₂X⁹⁴, —OCHX⁹⁴₂, —OCX⁹⁴ ₃, —OCH₂X⁹⁴, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁹⁵-substituted or unsubstituted alkyl,R⁹⁵-substituted or unsubstituted heteroalkyl, R⁹⁵-substituted orunsubstituted cycloalkyl, R⁹⁵-substituted or unsubstitutedheterocycloalkyl, R⁹⁵-substituted or unsubstituted aryl, orR⁹⁵-substituted or unsubstituted heteroaryl. X⁹⁴ is halogen. Inembodiments, X⁹⁴ is F.

In embodiments, each R²⁵ is independently hydrogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, R⁹⁶-substituted or unsubstituted alkyl,R⁹⁶-substituted or unsubstituted heteroalkyl, R⁹⁶-substituted orunsubstituted cycloalkyl, R⁹⁶-substituted or unsubstitutedheterocycloalkyl, R⁹⁶-substituted or unsubstituted aryl, orR⁹⁶-substituted or unsubstituted heteroaryl. Each X is independently —F,—Cl, —Br, or —I. In embodiments, X is —F.

R⁹⁶ is independently oxo, halogen, —CX⁹⁶ ₃, —CHX⁹⁶ ₂, —CH₂X⁹⁶, —OCHX⁹⁶₂, —OCX⁹⁶ ₃, —OCH₂X⁹⁶, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁹⁷-substituted or unsubstituted alkyl,R⁹⁷-substituted or unsubstituted heteroalkyl, R⁹⁷-substituted orunsubstituted cycloalkyl, R⁹⁷-substituted or unsubstitutedheterocycloalkyl, R⁹⁷-substituted or unsubstituted aryl, orR⁹⁷-substituted or unsubstituted heteroaryl. X⁹⁶ is halogen. Inembodiments, X⁹⁶ is F.

R⁹⁷ is independently oxo, halogen, —CX⁹⁷ ₃, —CHX⁹⁷ ₂, —CH₂X⁹⁷, —OCHX⁹⁷₂, —OCX⁹⁷ ₃, —OCH₂X⁹⁷, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁹⁸-substituted or unsubstituted alkyl,R⁹⁸-substituted or unsubstituted heteroalkyl, R⁹⁸-substituted orunsubstituted cycloalkyl, R⁹⁸-substituted or unsubstitutedheterocycloalkyl, R⁹⁸-substituted or unsubstituted aryl, orR⁹⁸-substituted or unsubstituted heteroaryl. X⁹⁷ is halogen. Inembodiments, X⁹⁷ is F.

In embodiments, each R²⁶ is independently hydrogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, R⁹⁹-substituted or unsubstituted alkyl,R⁹⁹-substituted or unsubstituted heteroalkyl, R⁹⁹-substituted orunsubstituted cycloalkyl, R⁹⁹-substituted or unsubstitutedheterocycloalkyl, R⁹⁹-substituted or unsubstituted aryl, orR⁹⁹-substituted or unsubstituted heteroaryl. Each X is independently —F,—Cl, —Br, or —I. In embodiments, X is —F.

R⁹⁹ is independently oxo, halogen, —CX⁹⁹ ₃, —CHX⁹⁹ ₂, —CH₂X⁹⁹, —OCHX⁹⁹₂, —OCX⁹⁹ ₃, —OCH₂X⁹⁹, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R¹⁰⁰-substituted or unsubstituted alkyl,R¹⁰⁰-substituted or unsubstituted heteroalkyl, R¹⁰⁰-substituted orunsubstituted cycloalkyl, R¹⁰⁰-substituted or unsubstitutedheterocycloalkyl, R¹⁰⁰-substituted or unsubstituted aryl, orR¹⁰⁰-substituted or unsubstituted heteroaryl. X⁹⁹ is halogen. Inembodiments, X⁹⁹ is F.

R¹⁰⁰ is independently oxo, halogen, —CX¹⁰⁰ ₃, —CHX¹⁰⁰ ₂, —CH₂X¹⁰⁰,—OCHX¹⁰⁰ ₂, —OCX¹⁰⁰ ₃, —OCH₂X¹⁰⁰, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R¹⁰¹-substituted or unsubstitutedalkyl, R¹⁰¹-substituted or unsubstituted heteroalkyl, R¹⁰¹-substitutedor unsubstituted cycloalkyl, R¹⁰¹-substituted or unsubstitutedheterocycloalkyl, R¹⁰¹-substituted or unsubstituted aryl, orR¹⁰¹-substituted or unsubstituted heteroaryl. X¹⁰⁰ is halogen. Inembodiments, X¹⁰⁰ is F.

In embodiments, each R²⁷ is independently hydrogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, R¹⁰²-substituted or unsubstituted alkyl,R¹⁰²-substituted or unsubstituted heteroalkyl, R¹⁰²-substituted orunsubstituted cycloalkyl, R¹⁰²-substituted or unsubstitutedheterocycloalkyl, R¹⁰²-substituted or unsubstituted aryl, orR¹⁰²-substituted or unsubstituted heteroaryl. Each X is independently—F, —Cl, —Br, or —I. In embodiments, X is —F.

R¹⁰² is independently oxo, halogen, —CX¹⁰² ₃, —CHX¹⁰² ₂, —CH₂X¹⁰²,—OCHX¹⁰² ₂, —OCX¹⁰² ₃, —OCH₂X¹⁰², —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R¹⁰³-substituted or unsubstitutedalkyl, R¹⁰³-substituted or unsubstituted heteroalkyl, R¹⁰³-substitutedor unsubstituted cycloalkyl, R¹⁰³-substituted or unsubstitutedheterocycloalkyl, R¹⁰³-substituted or unsubstituted aryl, orR¹⁰³-substituted or unsubstituted heteroaryl. X¹⁰² is halogen. Inembodiments, X¹⁰² is F.

R¹⁰³ is independently oxo, halogen, —CX¹⁰³ ₃, —CHX¹⁰³ ₂, —CH₂X¹⁰³,—OCHX¹⁰³ ₂, —OCX¹⁰³ ₃, —OCH₂X¹⁰³, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R¹⁰⁴-substituted or unsubstitutedalkyl, R¹⁰⁴-substituted or unsubstituted heteroalkyl, R¹⁰⁴-substitutedor unsubstituted cycloalkyl, R¹⁰⁴-substituted or unsubstitutedheterocycloalkyl, R¹⁰⁴-substituted or unsubstituted aryl, orR¹⁰⁴-substituted or unsubstituted heteroaryl. X¹⁰³ is halogen. Inembodiments, X¹⁰³ is F.

In embodiments, each R²⁸ is independently hydrogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, R¹⁰⁵-substituted or unsubstituted alkyl,R¹⁰⁵-substituted or unsubstituted heteroalkyl, R¹⁰⁵-substituted orunsubstituted cycloalkyl, R¹⁰⁵-substituted or unsubstitutedheterocycloalkyl, R¹⁰⁵-substituted or unsubstituted aryl, orR¹⁰⁵-substituted or unsubstituted heteroaryl. Each X is independently—F, —Cl, —Br, or —I. In embodiments, X is —F.

R¹⁰⁵ is independently oxo, halogen, —CX¹⁰⁵ ₃, —CHX¹⁰⁵ ₂, —CH₂X¹⁰⁵,—OCHX¹⁰⁵ ₂, —OCX¹⁰⁵ ₃, —OCH₂X¹⁰⁵, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R¹⁰⁶-substituted or unsubstitutedalkyl, R¹⁰⁶-substituted or unsubstituted heteroalkyl, R¹⁰⁶-substitutedor unsubstituted cycloalkyl, R¹⁰⁶-substituted or unsubstitutedheterocycloalkyl, R¹⁰⁶-substituted or unsubstituted aryl, orR¹⁰⁶-substituted or unsubstituted heteroaryl. X¹⁰⁵ is halogen. Inembodiments, X¹⁰⁵ is F.

R¹⁰⁶ is independently oxo, halogen, —CX¹⁰⁶ ₃, —CHX¹⁰⁶ ₂, —CH₂X¹⁰⁶,—OCHX¹⁰⁶ ₂, —OCX¹⁰⁶ ₃, —OCH₂X¹⁰⁶, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R¹⁰⁷-substituted or unsubstitutedalkyl, R¹⁰⁷-substituted or unsubstituted heteroalkyl, R¹⁰⁷-substitutedor unsubstituted cycloalkyl, R¹⁰⁷-substituted or unsubstitutedheterocycloalkyl, R¹⁰⁷-substituted or unsubstituted aryl, orR¹⁰⁷-substituted or unsubstituted heteroaryl. X¹⁰⁶ is halogen. Inembodiments, X¹⁰⁶ is F.

In embodiments, R^(1A) is independently halogen, —CN, —OR^(1B),—SR^(1B), —NR^(1C)R^(1D), —NR^(1C)C(O)R^(1B), —C(O)NR^(1C)R^(1D),—CO₂R^(1B), R¹⁰⁸-substituted or unsubstituted alkyl, or R¹⁰⁸-substitutedor unsubstituted heteroalkyl.

In embodiments, R¹⁰⁸ is independently oxo, halogen, —CX¹⁰⁸ ₃, —CHX¹⁰⁸ ₂,—CH₂X¹⁰⁸, —OCHX¹⁰⁸ ₂, —OCX¹⁰⁸ ₃, —OCH₂X¹⁰⁸, —CN, —OH, —NH₂, —CO OH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R¹⁰⁹-substituted orunsubstituted alkyl, R¹⁰⁹-substituted or unsubstituted heteroalkyl,R¹⁰⁹-substituted or unsubstituted cycloalkyl, R¹⁰⁹-substituted orunsubstituted heterocycloalkyl, R¹⁰⁹-substituted or unsubstituted aryl,or R¹⁰⁹-substituted or unsubstituted heteroaryl. X¹⁰⁸ is halogen. Inembodiments, X¹⁰⁸ is F.

In embodiments, R¹⁰⁹ is independently oxo, halogen, —CX¹⁰⁹ ₃, —CHX¹⁰⁹ ₂,—CH₂X¹⁰⁹, —OCHX¹⁰⁹ ₂, —OCX¹⁰⁹ ₃, —OCH₂X¹⁰⁹, —CN, —OH, —NH₂, —CO OH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R¹¹⁰-substituted orunsubstituted alkyl, R¹¹⁰-substituted or unsubstituted heteroalkyl,R¹¹⁰-substituted or unsubstituted cycloalkyl, R¹¹⁰-substituted orunsubstituted heterocycloalkyl, R¹¹⁰-substituted or unsubstituted aryl,or R¹¹⁰-substituted or unsubstituted heteroaryl. X¹⁰⁹ is halogen. Inembodiments, X¹⁰⁹ is F.

In embodiments, R^(1B) is independently hydrogen, R¹¹¹-substituted orunsubstituted alkyl, R¹¹¹-substituted or unsubstituted heteroalkyl,R¹¹¹-substituted or unsubstituted cycloalkyl, R¹¹¹-substituted orunsubstituted heterocycloalkyl, R¹¹¹-substituted or unsubstituted aryl,or R¹¹¹-substituted or unsubstituted heteroaryl.

In embodiments, R¹¹¹ is independently oxo, halogen, —CX¹¹¹ ₃, —CHX¹¹¹ ₂,—CH₂X¹¹¹, —OCHX¹¹¹ ₂, —OCX¹¹¹ ₃, —OCH₂X¹¹¹, —CN, —OH, —NH₂, —CO OH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R¹¹²-substituted orunsubstituted alkyl, R¹¹²-substituted or unsubstituted heteroalkyl,R¹¹²-substituted or unsubstituted cycloalkyl, R¹¹²-substituted orunsubstituted heterocycloalkyl, R¹¹²-substituted or unsubstituted aryl,or R¹¹²-substituted or unsubstituted heteroaryl. X¹¹¹ is halogen. Inembodiments, X¹¹¹ is F.

In embodiments, R¹¹² is independently oxo, halogen, —CX¹¹² ₃, —CHX¹¹² ₂,—CH₂X¹¹², —OCHX¹¹² ₂, —OCX¹¹² ₃, —OCH₂X¹¹², —CN, —OH, —NH₂, —CO OH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R¹¹³-substituted orunsubstituted alkyl, R¹¹³-substituted or unsubstituted heteroalkyl,R¹¹³-substituted or unsubstituted cycloalkyl, R¹¹³-substituted orunsubstituted heterocycloalkyl, R¹¹³-substituted or unsubstituted aryl,or R¹¹³-substituted or unsubstituted heteroaryl. X¹¹² is halogen. Inembodiments, X¹¹² is F.

In embodiments, R^(1C) is independently hydrogen, R¹¹⁴-substituted orunsubstituted alkyl, R¹¹⁴-substituted or unsubstituted heteroalkyl,R¹¹⁴-substituted or unsubstituted cycloalkyl, R¹¹⁴-substituted orunsubstituted heterocycloalkyl, R¹¹⁴-substituted or unsubstituted aryl,or R¹¹⁴-substituted or unsubstituted heteroaryl;

In embodiments, R¹¹⁴ is independently oxo, halogen, —CX¹¹⁴ ₃, —CHX¹¹⁴ ₂,—CH₂X¹¹⁴, —OCHX¹¹⁴ ₂, —OCX¹¹⁴ ₃, —OCH₂X¹¹⁴, —CN, —OH, —NH₂, —CO OH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R¹¹⁵-substituted orunsubstituted alkyl, R¹¹⁵-substituted or unsubstituted heteroalkyl,R¹¹⁵-substituted or unsubstituted cycloalkyl, R¹¹⁵-substituted orunsubstituted heterocycloalkyl, R¹¹⁵-substituted or unsubstituted aryl,or R¹¹⁵-substituted or unsubstituted heteroaryl. X¹¹⁴ is halogen. Inembodiments, X¹¹⁴ is F.

In embodiments, R¹¹⁵ is independently oxo, halogen, —CX¹¹⁵ ₃, —CHX¹¹⁵ ₂,—CH₂X¹¹⁵, —OCHX¹⁵², —OCX¹¹⁵ ₃, —OCH₂X¹¹⁵, —CN, —OH, —NH₂, —CO OH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R¹¹⁶-substituted orunsubstituted alkyl, R¹¹⁶-substituted or unsubstituted heteroalkyl,R¹¹⁶-substituted or unsubstituted cycloalkyl, R¹¹⁶-substituted orunsubstituted heterocycloalkyl, R¹¹⁶-substituted or unsubstituted aryl,or R¹¹⁶-substituted or unsubstituted heteroaryl. X¹¹⁵ is halogen. Inembodiments, X¹¹⁵ is F.

In embodiments, R^(1D) is independently R¹¹⁷-substituted orunsubstituted alkyl, R¹¹⁷-substituted or unsubstituted heteroalkyl,R¹¹⁷-substituted or unsubstituted cycloalkyl, R¹¹⁷-substituted orunsubstituted heterocycloalkyl, R¹¹⁷-substituted or unsubstituted aryl,or R¹¹⁷-substituted or unsubstituted heteroaryl.

In embodiments, R¹¹⁷ is independently oxo, halogen, —CX¹¹⁷ ₃, —CHX¹¹⁷ ₂,—CH₂X¹¹⁷, —OCHX¹¹⁷ ₂, —OCX¹¹⁷ ₃, —OCH₂X¹¹⁷, —CN, —OH, —NH₂, —CO OH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R¹¹⁸-substituted orunsubstituted alkyl, R¹¹⁸-substituted or unsubstituted heteroalkyl,R¹¹⁸-substituted or unsubstituted cycloalkyl, R¹¹⁸-substituted orunsubstituted heterocycloalkyl, R¹¹⁸-substituted or unsubstituted aryl,or R¹¹⁸-substituted or unsubstituted heteroaryl. X¹¹⁷ is halogen. Inembodiments, X¹¹⁷ is F.

In embodiments, R¹¹⁸ is independently oxo, halogen, —CX¹¹⁸ ₃, —CHX¹¹⁸ ₂,—CH₂X¹¹⁸, —OCHX¹¹⁸ ₂, —OCX¹¹⁸ ₃, —OCH₂X¹¹⁸, —CN, —OH, —NH₂, —CO OH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R¹¹⁹-substituted orunsubstituted alkyl, R¹¹⁹-substituted or unsubstituted heteroalkyl,R¹¹⁹-substituted or unsubstituted cycloalkyl, R¹¹⁹-substituted orunsubstituted heterocycloalkyl, R¹¹⁹-substituted or unsubstituted aryl,or R¹¹⁹-substituted or unsubstituted heteroaryl. X¹¹⁸ is halogen. Inembodiments, X¹¹⁸ is F.

In embodiments, R^(1C) and R^(1D) attached to the same nitrogen atomoptionally combine to form a R¹²⁰-substituted or unsubstitutedheterocycloalkyl.

In embodiments, R¹²⁰ is independently oxo, halogen, —CX¹²⁰ ₃, —CHX¹²⁰ ₂,—CH₂X¹²⁰, —OCHX¹²⁰ ₂, —OCX¹²⁰ ₃, —OCH₂X¹²⁰, —CN, —OH, —NH₂, —CO OH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R¹²¹-substituted orunsubstituted alkyl, R¹²¹-substituted or unsubstituted heteroalkyl,R¹²¹-substituted or unsubstituted cycloalkyl, R¹²¹-substituted orunsubstituted heterocycloalkyl, R¹²¹-substituted or unsubstituted aryl,or R¹²¹-substituted or unsubstituted heteroaryl. X¹²⁰ is halogen. Inembodiments, X¹²⁰ is F.

In embodiments, R¹²¹ is independently oxo, halogen, —CX¹²¹ ₃, —CHX¹²¹ ₂,—CH₂X¹²¹, —OCHX¹²¹ ₂, —OCX¹²¹ ₃, —OCH₂X¹²¹, —CN, —OH, —NH₂, —CO OH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R¹²²-substituted orunsubstituted alkyl, R¹²²-substituted or unsubstituted heteroalkyl,R¹²²-substituted or unsubstituted cycloalkyl, R¹²²-substituted orunsubstituted heterocycloalkyl, R¹²²-substituted or unsubstituted aryl,or R¹²²-substituted or unsubstituted heteroaryl. X¹²¹ is halogen. Inembodiments, X¹²¹ is F.

In embodiments, R^(2A) is independently —NR^(2B)R^(2C), R¹²³-substitutedor unsubstituted cycloalkyl, R¹²³-substituted or unsubstitutedheterocycloalkyl, R¹²³-substituted or unsubstituted aryl, orR¹²³-substituted or unsubstituted heteroaryl.

In embodiments, R¹²³ is independently oxo, halogen, —CX¹²³ ₃, —CHX¹²³ ₂,—CH₂X¹²³, —OCHX¹²³ ₂, —OCX¹²³ ₃, —OCH₂X¹²³, —CN, —OH, —NH₂, —CO OH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R¹²⁴-substituted orunsubstituted alkyl, R¹²⁴-substituted or unsubstituted heteroalkyl,R¹²⁴-substituted or unsubstituted cycloalkyl, R¹²⁴-substituted orunsubstituted heterocycloalkyl, R¹²⁴-substituted or unsubstituted aryl,or R¹²⁴-substituted or unsubstituted heteroaryl. X¹²³ is halogen. Inembodiments, X¹²³ is F.

In embodiments, R¹²⁴ is independently oxo, halogen, —CX¹²⁴ ₃, —CHX¹²⁴ ₂,—CH₂X¹²⁴, —OCHX¹²⁴ ₂, —OCX¹²⁴ ₃, —OCH₂X¹²⁴, —CN, —OH, —NH₂, —CO OH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R¹²⁵-substituted orunsubstituted alkyl, R¹²⁵-substituted or unsubstituted heteroalkyl,R¹²⁵-substituted or unsubstituted cycloalkyl, R¹²⁵-substituted orunsubstituted heterocycloalkyl, R¹²⁵-substituted or unsubstituted aryl,or R¹²⁵-substituted or unsubstituted heteroaryl. X¹²⁴ is halogen. Inembodiments, X¹²⁴ is F.

In embodiments, R^(2B) is independently hydrogen, R¹²⁶-substituted orunsubstituted alkyl, R¹²⁶-substituted or unsubstituted heteroalkyl,R¹²⁶-substituted or unsubstituted cycloalkyl, R¹²⁶-substituted orunsubstituted heterocycloalkyl, R¹²⁶-substituted or unsubstituted aryl,or R¹²⁶-substituted or unsubstituted heteroaryl.

In embodiments, R¹²⁶ is independently oxo, halogen, —CX¹²⁶ ₃, —CHX¹²⁶ ₂,—CH₂X¹²⁶, —OCHX¹²⁶ ₂, —OCX¹²⁶ ₃, —OCH₂X¹²⁶, —CN, —OH, —NH₂, —CO OH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R¹²⁷-substituted orunsubstituted alkyl, R¹²⁷-substituted or unsubstituted heteroalkyl,R¹²⁷-substituted or unsubstituted cycloalkyl, R¹²⁷-substituted orunsubstituted heterocycloalkyl, R¹²⁷-substituted or unsubstituted aryl,or R¹²⁷-substituted or unsubstituted heteroaryl. X¹²⁶ is halogen. Inembodiments, X¹²⁶ is F.

In embodiments, R¹²⁷ is independently oxo, halogen, —CX¹²⁷ ₃, —CHX¹²⁷ ₂,—CH₂X¹²⁷, —OCHX¹²⁷ ₂, —OCX¹²⁷ ₃, —OCH₂X¹²⁷, —CN, —OH, —NH₂, —CO OH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R¹²⁸-substituted orunsubstituted alkyl, R¹²⁸-substituted or unsubstituted heteroalkyl,R¹²⁸-substituted or unsubstituted cycloalkyl, R¹²⁸-substituted orunsubstituted heterocycloalkyl, R¹²⁸-substituted or unsubstituted aryl,or R¹²⁸-substituted or unsubstituted heteroaryl. X¹²⁷ is halogen. Inembodiments, X¹²⁷ is F.

In embodiments, R^(2C) is independently hydrogen, R¹²⁶-substituted orunsubstituted alkyl, R¹²⁶-substituted or unsubstituted heteroalkyl,R¹²⁶-substituted or unsubstituted cycloalkyl, R¹²⁶-substituted orunsubstituted heterocycloalkyl, R¹²⁶-substituted or unsubstituted aryl,or R¹²⁶-substituted or unsubstituted heteroaryl.

In embodiments, R¹²⁶ is independently oxo, halogen, —CX¹²⁶ ₃, —CHX¹²⁶ ₂,—CH₂X¹²⁶, —OCHX¹²⁶ ₂, —OCX¹²⁶ ₃, —OCH₂X¹²⁶, —CN, —OH, —NH₂, —CO OH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R¹³⁰-substituted orunsubstituted alkyl, R¹³⁰-substituted or unsubstituted heteroalkyl,R¹³⁰-substituted or unsubstituted cycloalkyl, R¹³⁰-substituted orunsubstituted heterocycloalkyl, R¹³⁰-substituted or unsubstituted aryl,or R¹³⁰-substituted or unsubstituted heteroaryl. X¹²⁹ is halogen. Inembodiments, X¹²⁹ is F.

In embodiments, R¹³⁰ is independently oxo, halogen, —CX¹³⁰ ₃, —CHX¹³⁰ ₂,—CH₂X¹³⁰, —OCHX¹³⁰ ₂, —OCX¹³⁰ ₃, —OCH₂X¹³⁰, —CN, —OH, —NH₂, —CO OH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R¹³¹-substituted orunsubstituted alkyl, R¹³¹-substituted or unsubstituted heteroalkyl,R¹³¹-substituted or unsubstituted cycloalkyl, R¹³¹-substituted orunsubstituted heterocycloalkyl, R¹³¹-substituted or unsubstituted aryl,or R¹³¹-substituted or unsubstituted heteroaryl. X¹³⁰ is halogen. Inembodiments, X¹³⁰ is F.

In embodiments, R^(2B) and R^(2C) attached to the same nitrogen atomoptionally combine to form a R¹³²-substituted or unsubstitutedheterocycloalkyl.

In embodiments, R¹³² is independently oxo, halogen, —CX¹³² ₃, —CHX¹³² ₂,—CH₂X¹³², —OCHX¹³² ₂, —OCX¹³² ₃, —OCH₂X¹³², —CN, —OH, —NH₂, —CO OH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R¹³³-substituted orunsubstituted alkyl, R¹³³-substituted or unsubstituted heteroalkyl,R¹³³-substituted or unsubstituted cycloalkyl, R¹³³-substituted orunsubstituted heterocycloalkyl, R¹³³-substituted or unsubstituted aryl,or R¹³³-substituted or unsubstituted heteroaryl. X¹³² is halogen. Inembodiments, X¹³² is F.

In embodiments, R¹³³ is independently oxo, halogen, —CX¹³³ ₃, —CHX¹³³ ₂,—CH₂X¹³³, —OCHX¹³³ ₂, —OCX¹³³ ₃, —OCH₂X¹³³, —CN, —OH, —NH₂, —CO OH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R¹³⁴-substituted orunsubstituted alkyl, R¹³⁴-substituted or unsubstituted heteroalkyl,R¹³⁴-substituted or unsubstituted cycloalkyl, R¹³⁴-substituted orunsubstituted heterocycloalkyl, R¹³⁴-substituted or unsubstituted aryl,or R¹³⁴-substituted or unsubstituted heteroaryl. X¹³³ is halogen. Inembodiments, X¹³³ is F.

R³¹, R³⁴, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴⁴, R⁴⁷, R⁵⁰, R⁵³, R⁵⁶, R⁵⁹, R⁶²,R⁶⁵, R⁶⁸, R⁷¹, R⁷⁴, R⁷⁷, R⁸⁰, R⁸³, R⁸⁶, R⁸⁹, R⁹², R⁹⁵, R⁹⁸, R¹⁰¹, R¹⁰⁴,R¹⁰⁷, R¹¹⁰, R¹¹³, R¹¹⁶, R¹¹⁹, R¹²², R¹²⁵, R¹²⁸, and R¹³¹ areindependently hydrogen, oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, orunsubstituted heteroaryl.

In some embodiments, a compound as described herein may include multipleinstances of X and/or other variables. For example, where each X isdifferent, they may be referred to as, for example, X^(a), X^(b), X^(c),X^(d), X^(e), X^(f), X^(g), X^(h), X^(i), X^(j), X^(k), X^(l), X^(m),X^(n), X^(o), X^(p), X^(q), X^(r), X^(s), X^(t), X^(u), X^(v), X^(w),X^(x), X^(y), X^(z), X^(aa), X^(bb), X^(cc), X^(dd), X^(ee), X^(ff),X^(gg), X^(hh), X^(ii), X^(jj), X^(kk), X^(ll), X^(mm), X^(nn), X^(oo),X^(pp), X^(qq), X^(rr), X^(ss), X^(tt), X^(uu), X^(vv), X^(ww), X^(xx),X^(yy), X^(zz), X^(aaa), X^(bbb), X^(ccc), X^(ddd), X^(eee), X^(fff),X^(ggg), X^(hhh), X^(iii), X^(jjj), X^(kkk), X^(lll), X^(mmm), andX^(nnn), where the definition of X is assumed for each of X^(a), X^(b),X^(c), X^(d), X^(e), X^(f), X^(g), X^(h), X^(i), X^(j), X^(k), X^(l),X^(m), X^(n), X^(o), X^(p), X^(q), X^(r), X^(s), X^(t), X^(u), X^(v),X^(w), X^(x), X^(y), X^(z), X^(aa), X^(bb), X^(cc), X^(dd), X^(ee),X^(ff), X^(gg), X^(hh), X^(ii), X^(jj), X^(kk), X^(ll), X^(mm), X^(nn),X^(oo), X^(pp), X^(qq), X^(rr), X^(ss), X^(tt), X^(uu), X^(vv), X^(ww),X^(xx), X^(yy), X^(zz), X^(aaa), X^(bbb), X^(ccc), X^(ddd), X^(eee),X^(fff), X^(ggg), X^(hhh), X^(iii), X^(jjj), X^(kkk), X^(lll), X^(mmm),and X^(nnn). The variables used within a definition of X and/or othervariables that appear at multiple instances and are different maysimilarly be appropriately labeled to distinguish each group for greaterclarity.

In some embodiments, the compound is a compound described herein (e.g.,in an aspect, embodiment, example, claim, table, scheme, drawing, orfigure).

In embodiments, unless otherwise indicated, a compound described hereinis a racemic mixture of all stereoisomers. In embodiments, unlessotherwise indicated, a compound described herein is a racemic mixture ofall enantiomers. In embodiments, unless otherwise indicated, a compounddescribed herein is a racemic mixture of two opposite stereoisomers. Inembodiments, unless otherwise indicated, a compound described herein isa racemic mixture of two opposite enantiomers. In embodiments, unlessotherwise indicated, a compound described herein is a singlestereoisomer. In embodiments, unless otherwise indicated, a compounddescribed herein is a single enantiomer. In embodiments, the compound isa compound described herein (e.g., in an aspect, embodiment, example,figure, table, scheme, or claim).

In embodiments, a compound as described herein may be obtained or usedas a pharmaceutically acceptable salt, polymorph, solvate, tautomer,pharmaceutically acceptable prodrug or N-oxide thereof.

III. Pharmaceutical Compositions

In an aspect is provided a pharmaceutical composition including acompound described herein, or pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient.

In embodiments of the pharmaceutical compositions, the compound, orpharmaceutically acceptable salt thereof, is included in atherapeutically effective amount.

In embodiments of the pharmaceutical compositions, the pharmaceuticalcomposition includes a second agent (e.g. therapeutic agent). Inembodiments of the pharmaceutical compositions, the pharmaceuticalcomposition includes a second agent (e.g. therapeutic agent) in atherapeutically effective amount. In embodiments of the pharmaceuticalcompositions, the second agent is an agent for treating cancer. Inembodiments, the second agent is an anti-cancer agent. In embodiments,the second agent is a chemotherapeutic.

IV. Methods of Synthesis

In some embodiments, the syntheses of compounds described herein areaccomplished using means described in the chemical literature, using themethods described herein, or by a combination thereof. In addition,solvents, temperatures and other reaction conditions presented hereinmay vary.

In other embodiments, the starting materials and reagents used for thesynthesis of the compounds described herein are synthesized or areobtained from commercial sources, such as, but not limited to,Sigma-Aldrich, FisherScientific (Fisher Chemicals), and AcrosOrganics.

In further embodiments, the compounds described herein, and otherrelated compounds having different substituents are synthesized usingtechniques and materials described herein as well as those that arerecognized in the field, such as described, for example, in Fieser andFieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley andSons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989), March, Advanced OrganicChemistry 4th Ed., (Wiley 1992); Carey and Sundberg, Advanced OrganicChemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green andWuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (allof which are incorporated by reference for such disclosure). Generalmethods for the preparation of compounds as disclosed herein may bederived from reactions and the reactions may be modified by the use ofappropriate reagents and conditions, for the introduction of the variousmoieties found in the formulae as provided herein. As a guide thefollowing synthetic methods may be utilized.

In the reactions described, it may be necessary to protect reactivefunctional groups, for example hydroxy, amino, imino, thio or carboxygroups, where these are desired in the final product, in order to avoidtheir unwanted participation in reactions. A detailed description oftechniques applicable to the creation of protecting groups and theirremoval are described in Greene and Wuts, Protective Groups in OrganicSynthesis, 3rd Ed., John Wiley & Sons, New York, N.Y., 1999, andKocienski, Protective Groups, Thieme Verlag, New York, N.Y., 1994, whichare incorporated herein by reference for such disclosure).

V. Methods of Treatment

In an aspect is provided a method of treating a disease or conditionincluding administering to a subject in need thereof an effective amountof a compound described herein.

In embodiments, the disease or condition is diabetes, heart disease,coronary artery disease, hyperlipidemia, lipodystrophy, insulinresistance, rheumatic disease, atherosclerosis, myocardial infarction,stroke, high blood pressure (hypertension), obesity, elevated fastingplasma glucose, high serum triglycerides, elevated blood cholesterol,cardiac hypertrophy, heart failure (e.g., hypertrophy-induced heartfailure) or metabolic syndrome.

In an aspect is provided a method of treating a disease associated withlow molecular weight protein tyrosine phosphatase (LMPTP) activityincluding administering to a subject in need thereof an effective amountof a compound described herein. In embodiments, the disease isassociated with aberrant low molecular weight protein tyrosinephosphatase (LMPTP) activity. For example, studies have shown thatinhibition of low molecular weight protein tyrosine phosphatase (LMPTP)activity may be a target for cardiac diseases (e.g., heart failure).See, e.g., Wade et al., J. Pathol., 2015, pages 1-13 (DOI:10.1002/path.4594), which is hereby incorporated by reference in itsentirety.

In embodiments, the method includes administering a second agent (e.g.therapeutic agent). In embodiments, the method includes administering asecond agent (e.g. therapeutic agent) in a therapeutically effectiveamount. Examples of a second agent include therapeutic agents known inthe art for the treatment of diabetes, heart disease, coronary arterydisease, hyperlipidemia, lipodystrophy, insulin resistance, rheumaticdisease, atherosclerosis, myocardial infarction, stroke, high bloodpressure (hypertension), obesity, elevated fasting plasma glucose, highserum triglycerides, elevated blood cholesterol, cardiac hypertrophy,heart failure (e.g., hypertrophy-induced heart failure) or metabolicsyndrome. Thus, in embodiments, the method includes administering to asubject in need thereof an effective amount of a compound describedherein in combination with a second therapeutic agent for the treatmentof diabetes, heart disease, coronary artery disease, hyperlipidemia,lipodystrophy, insulin resistance, rheumatic disease, atherosclerosis,myocardial infarction, stroke, high blood pressure (hypertension),obesity, elevated fasting plasma glucose, high serum triglycerides,elevated blood cholesterol, cardiac hypertrophy, heart failure (e.g.,hypertrophy-induced heart failure) or metabolic syndrome.

VI. Methods of Inhibition

In an aspect is provided a method of inhibiting low molecular weightprotein tyrosine phosphatase (LMPTP) activity including contacting thelow molecular weight protein tyrosine phosphatase (LMPTP) with acompound described herein. In embodiments, the low molecular weightprotein tyrosine phosphatase (LMPTP) is a human low molecular weightprotein tyrosine phosphatase (LMPTP).

In embodiments, the inhibition is competitive inhibition. Inembodiments, the inhibition is non-competitive inhibition. Inembodiments, the inhibition is uncompetitive inhibition. In embodiments,the inhibition is irreversible. In embodiments, the inhibition isreversible.

In embodiments, the compound, or pharmaceutically acceptable saltthereof, is an allosteric inhibitor.

VII. Examples

In some embodiments, compounds described herein are prepared as shown inScheme 1.

The synthesis of compound VI can be accomplished by the reactionsillustrated in Scheme 1. Treatment of Compound I with an acid chlorideII containing an amine base at temperatures between 0° C. and 50° C. ina solvent such as dichlormethane (DCM) produced compound III.Alternatively, activation of the carboxylic acid of formula II with acoupling reagent such as 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide(EDC) and Hydroxybenzotriazole (HOBt) in a solvent such as DMF oracetonitrile containing an amine base such as N,N-Diisopropylethylamine,triethylamine or other organic bases followed by treatment of thismixture with compound I gives rise to compounds of formula III.Substitution of the coupling reagent EDC by 1-Propanephosphonicanhydride solution,2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P),carbonyliimidazole, BOP reagent, dicyclohexylcarbodimide (DCC), or HATUproduces compound III.

Treatment of compound III with a strong base such as potassiumt-butoxide, sodium hydride in a solvent such as tert-butanol, DMF orDMSO at temperatures between 0° C. and 100° C. produced compound IV.Compound IV when treated with phosphorus oxychloride or thionyl chlorideat temperatures between 25° C. and 100° C. produced compound V. Finally,treatment compound V in an inert organic solvent such as THF, DMF, DMAcontaining an organic base such as triethylamine, or strong base such aspotassium t-butoxide, sodium hydride or potassium hydride with analcohol or amine compound of formula HZR₂ produces compounds of formulaVI. The reaction is preferably carried out at temperatures between 25°C. and 150° C.

Preparation of Tert-Butyl Piperazine-1-Carboxylates Structure III

General Procedure A Example A1: Preparation ofN-(2-Acetylphenyl)-4-Methoxybenzamide

To a solution of 1-(2-aminophenyl)ethanone (5.0 g, 37 mmol) and DIPEA(13 mL, 74 mmol) in 200 mL of THF in an ice bath was added4-methoxybenzoyl chloride (7.5 mL, 56 mmol) dropwise. After 30 min at 0°C., the mixture was stirred at room temperature overnight and poured in50 mL of ice water. The precipitate was collected and washed with waterand then methanol. The solid was dried under vacuum to yield 8.0 g ofN-(2-acetylphenyl)-4-methoxybenzamide (80% yield). MS (EI) m/z 270[(M+1)+].

Preparation of Compounds of Structure IV

General Procedure B Example B1: Preparation of2-(4-methoxyphenyl)quinolin-4-ol

N-(2-acetylphenyl)-4-methoxybenzamide (4.0 g, 15 mmol) was suspended in100 mL of tert-butyl alcohol. Potassium tert-butoxide (3.3 g, 30 mmol)was added. The mixture was heated at 75° C. overnight at nitrogenatmosphere. When the reaction was determined to be complete by HPLC, thereaction mixture was cooled and poured into 50 mL of ice water. 10%aqueous HCl was added until pH=6. The solid was collected and washedseveral times with water to afford 3.1 g of2-(4-methoxyphenyl)quinolin-4-ol (84% yield). MS (EI) m/z 252 [(M+1)+].

Preparation of Compounds of Structure V

General Procedure C Example C1: Preparation of4-chloro-2-(4-methoxyphenyl)quinoline

2-(4-methoxyphenyl)quinolin-4-ol (3.1 g, 12.4 mmol) was added tophosphorus oxychloride POCl₃ (50 mL, 540 mmol) to give an dark solution,then several drops of DMF was added. The reaction was heated at 90° C.overnight. When the reaction was determined to be complete by HPLC, thereaction mixture was cooled to room temperature and concentrated underreduced pressure. The resulting oil was basified with 1N NaOH solution,extracted with ethyl acetate and dried over magnesium sulfate. Theorganic layer was concentrated under reduced pressure to the crudeproduct, which was chromatographed on silica gel and eluted with ethylacetate and dichoromethane (0:100 to 30:70 gradient) to yield 2.0 g ofproduct 4 (61% yield). ¹H NMR (400 MHz, DMSO-d) δ 3.84 (s, 3H), 7.09 (m,2H), 7.70 (m, 1H), 7.88 (m, 1H), 8.09 (m, 1H), 8.18 (m, 1H), 8.27 (m,2H), 8.36 (m, 1H). MS (EI) m/z[(M+1)+].

Preparation of Compounds of Structure VI

General Procedure D Example D1: Preparation of2-(4-methoxyphenyl)-N-(3-(piperidin-1-yl)propyl)quinolin-4-amine

Potassium tert-butoxide (50 mg, 0.5 mmol)) was added to a solution of4-chloro-2-(4-methoxy-phenyl)quinoline 4 (1.0 g, 3.7 mmol) and3-(Piperidin-1-yl)propan-1-amine (1.1 g, 7.7 mmol) in dry DMA (50 ml).The reaction was heated at 135° C. overnight at nitrogen atmosphere.When the reaction was determined to be complete by HPLC, the reactionmixture was cooled to room temperature and evaporated under vacuum togive a residue. 20 mL of water was added and extracted with chloroform.The organic layer was dried over magnesium sulfate and concentratedunder reduced pressure to give the crude product, which was subjected tobe purified by preparative HPLC to afford 0.8 g of2-(4-methoxyphenyl)-N-(3-(piperidin-1-yl)propyl)quinolin-4-amine (57%yield). ¹H NMR (400 MHz, DMSO-d) δ 1.44 (m, 2H), 1.60 (m, 4H), 1.97 (m,2H), 2.72 (m, 6H), 3.45 (m, 2H), 3.82 (s, 3H), 4.94 (s, 2H), 6.91 (s,1H), 7.04 (m, 2H), 7.39 (m, 2H), 7.61 (m, 1H), 7.82 (m, 1H), 8.13 (m,3H), 8.26 (s, 2H). ¹³C NMR (400 MHz, DMSO-d) δ (ppm) 22.8, 23.7, 24.1,53.0, 55.3, 94.5, 113.8, 117.7, 121.5, 123.6, 128.6, 129.3, 132.0,147.7, 150.9, 156.0, 160.2, 164.4. MS (EI) m/z 376 [(M+1)+].

In some embodiments, compounds described herein are prepared as shown inScheme 2.

The synthesis of compound XI can be accomplished by the reactionsillustrated in Scheme 2. A mixture of compound VII and compound VII whentreated with phosphorus oxychloride or thionyl chloride at temperaturesbetween 25° C. and 100° C. produced compound VIII. Suzuki coupling ofcompound VIII with an aromatic boronic acid IX employing standard Suzukicoupling conditions using a palladium zero species such as Pd(PPh₃)₄,with aqueous potassium carbonate or sodium carbonate in an inert solventsuch as acetonitrile or toluene produces Compound X. The reaction ispreferably carried out at temperatures between 25° C. and 150° C. Thepredominate isomer produced in this reaction is the C2 addition on thequinoline ring. Finally, treatment compound X in an inert organicsolvent such as THF, DMF, DMA containing an organic base such astriethylamine, or strong base such as potassium t-butoxide, sodiumhydride or potassium hydride with an alcohol or amine compound offormula HZR₂ produces compounds of formula XI. The reaction ispreferably carried out at temperatures between 25° C. and 150° C.

Preparation of Compounds of Structure VIII

General Procedure E Example E1: Preparation of 2,4-dichloroquinoline

Aniline (10 g, 108 mmol) and malonic acid (11 g, 108 mmol) was suspendedin POCl₃ (100 mL). The resulting mixture was stirred at 120° C.overnight. After cooling to room temperature, the mixture was pouredinto crushed ice while shaking. The mixture was partitioned betweenwater (150 mL) and EA (150 mL). The aqueous phase was extracted with EA(200 mL×2). The combined organic phase was washed with water (250 mL×2)and brine (250 mL), and dried over NaSO₄. After filtration, the solventwas removed, and the residue was purified by silica gel columnchromatography (PE/EA=50/1) to give 2,4-dichloroquinoline (4.3 g, yield:20%) as a white solid. MS (EI): m/z 197.8 [(M+1)+].

Preparation of Compounds of Structure X

General Procedure F Example F1: Preparation of4-chloro-2-(2-trifluoromethyl-phenyl)-quinoline

To a mixture of 2,4-dichloro-quinoline (300 mg, 1.51 mmol) in CH₃CN (12mL) and H₂O (4 mL), was added 2-(trifluoromethyl)phenyboronic acid (232mg, 1.66 mmol), K₂CO₃ (417 mg, 3.02 mmol) and Pd(PPh₃)₄ (36 mg, 0.03mmol). The suspension was degassed under reduced pressure and purgedwith N₂ atmosphere for several times. The mixture was stirred at 80° C.overnight. The mixture was partitioned between water (30 mL) and EA (30mL). The aqueous phase was extracted with EA (30 mL×2). The combinedorganic phase was washed with brine (80 mL×2) and dried over NaSO₄.After filtration, the solvent was removed, and the residue was purifiedby silica gel column chromatography (PE/EA=50/1) to give4-chloro-2-(2-trifluoromethyl-phenyl)-quinoline (400 mg, yield: 86%) asa white solid. MS (EI): m/z 308.3 [(M+1)+].

Preparation of Compounds of Structure XI

General Procedure G Example G1: Preparation of(3-piperidin-1-yl-propyl)-[2-(2-trifluoromethyl-phenyl)-quinolin-4-yl]-amine

To a mixture of 4-chloro-2-(2-trifluoromethyl-phenyl)-quinoline (61 mg,0.197 mmol) in DMA (2.5 mL), was added t-BuOK (1.3 mg, 0.012 mmol) and3-piperidin-1-yl-propylamine (112 mg, 0.788 mmol). The resulting mixturewas stirred for 4 hrs at 180° C. by microwave. The mixture waspartitioned between water (30 mL) and EA (30 mL), extracted with EA (30mL×2). The combined organic phase was washed with brine (60 mL×2) anddried over NaSO₄. After filtration, the solvent was removed, and theresidue was purified by prep-HPLC and lyophilized with 2N HCl to afford(3-piperidin-1-yl-propyl)-[2-(2-trifluoromethyl-phenyl)-quinolin-4-yl]-amine(10 mg, yield: 23%) as a white solid.

¹H NMR (400 MHz, CD₃OD): δ=8.03 (d, J=8.0 Hz, 1H), 7.74 (t, J=6.8 Hz,2H), 7.63-7.55 (m, 3H), 7.48 (d, J=7.6 Hz, 1H), 7.41-7.39 (m, 1H), 6.45(s, 1H), 3.31 (t, J=6.8 Hz, 2H), 2.43-2.40 (m, 6H), 1.87-1.84 (m, 2H),1.53-1.49 (m, 4H), 1.40-1.38 (m, 2H). MS (EI): m/z 414.2 [(M+1)+].

Example G2:(3-Piperidin-1-yl-propyl)-[2-(2-trifluoromethoxy-phenyl)-quinolin-4-yl]-amine

¹H NMR (400 MHz, CD₃OD): δ=8.47 (d, J=8.4 Hz, 1H), 7.93-7.90 (m, 1H),7.82 (d, J=9.2 Hz, 2H), 7.73-7.67 (m, 2H), 7.60-7.53 (m, 2H), 6.97 (s,1H), 3.68 (t, J=6.8 Hz, 2H), 3.51-3.46 (m, 2H), 3.21-3.16 (m, 2H),2.90-2.84 (m, 2H), 2.23-2.16 (m, 2H). 1.86-1.79 (m, 2H), 1.77-1.73 (m,3H), 1.44-1.41 (m, 1H). MS: m/z 430.2 [(M+1)+].

Example G3:(3-Piperidin-1-yl-propyl)-[2-(3-trifluoromethoxy-phenyl)-quinolin-4-yl]-amine

¹H NMR (400 MHz, CD₃OD): δ=8.42 (d, J=8.8 Hz, 1H), 7.94-7.88 (m, 3H),7.86 (s, 1H), 7.72-7.64 (m, 2H), 7.55 (d, J=7.2 Hz, 1H), 7.03 (s, 1H),3.74 (t, J=6.8 Hz, 2H), 3.50-3.47 (m, 2H), 3.21-3.17 (m, 2H), 2.89-2.84(m, 2H), 2.26-2.18 (m, 2H). 1.86-1.69 (m, 5H), 1.44-1.40 (m, 1H). MS:m/z 430.2 [(M+1)+].

Example G4:(3-Piperidin-1-yl-propyl)-[2-(4-trifluoromethoxy-phenyl)-quinolin-4-yl]-amine

¹H NMR (400 MHz, CD₃OD): δ=8.49 (d, J=8.4 Hz, 1H), 8.16 (dd, J=6.4, 2.4Hz, 2H), 8.05-8.03 (m, 2H), 7.81-7.78 (m, 1H), 7.63 (d, J=8.4 Hz, 2H),7.15 (s, 1H), 3.85 (t, J=7.2 Hz, 2H), 3.62-3.59 (m, 2H), 3.38-3.29 (m,2H), 3.00-2.98 (m, 2H), 2.35-2.30 (m, 2H), 1.97-1.84 (m, 5H), 1.59-1.55(m, 1H). MS: m/z 430.2 [(M+1)+].

Example G5: N,N-dimethyl-2-(4-(trifluoromethoxy)phenyl)quinolin-4-amine

¹H NMR (400 MHz, CD₃OD): δ=8.35 (d, J=8.4 Hz, 1H), 7.98 (d, J=8.8 Hz,2H), 7.91 (d, J=8.8 Hz, 1H), 7.87-7.85 (m, 1H), 7.60-7.56 (m, 1H), 7.49(d, J=8.4 Hz, 2H), 7.02 (s, 1H), 3.49 (s, 6H). MS: m/z 333.1[(M+1)+].

Example G6:[2-(2-Fluoro-phenyl)-quinolin-4-yl]-(3-piperidin-1-yl-propyl)-amine

¹H NMR (300 MHz, CDCl₃): δ=8.36 (d, J=8.4 Hz, 1H), 8.17 (d, J=8.1 Hz,1H), 8.05-8.01 (m, 1H), 7.67 (t, J=7.5 Hz, 1H), 7.50 (t, J=7.5 Hz, 1H),7.41-7.38 (m, 1H), 7.32-7.28 (m, 1H), 7.19-7.14 (m, 1H), 6.75 (s, 1H),3.65-3.62 (m, 2H), 3.03-2.92 (m, 4H), 2.24-2.20 (m, 2H), 2.15-1.90 (m,4H), 1.66-1.62 (m, 2H), 1.28-1.23 (m, 2H). MS: m/z 364.2 [(M+1)+].

Example G7:[2-(3-Fluoro-phenyl)-quinolin-4-yl]-(3-piperidin-1-yl-propyl)-amine

¹H NMR (400 MHz, CD₃OD): δ=8.55 (d, J=8.0 Hz, 1H), 8.08-7.99 (m, 2H),7.89-7.80 (m, 2H), 7.78-7.71 (m, 2H), 3.74 (td, J=8.8, 2.4 Hz, 1H), 7.16(s, 1H), 3.87 (t, J=6.8 Hz, 2H), 3.63-3.60 (m, 2H), 3.34-3.31 (m, 2H),3.03-2.97 (m, 2H), 2.39-2.34 (m, 2H). 1.99-1.87 (m, 5H), 1.57-1.54 (m,1H). MS: m/z 364.2 [(M+1)+].

Example G8:[2-(4-Fluoro-phenyl)-quinolin-4-yl]-(3-piperidin-1-yl-propyl)-amine

¹H NMR (400 MHz, CD₃OD): δ=8.53 (d, J=8.8 Hz, 1H), 8.13-8.10 (m, 2H),8.07-8.01 (m, 2H), 7.77 (t, J=8.0 Hz, 1H), 7.46 (t, J=8.8 Hz, 2H), 7.13(s, 1H), 3.86 (t, J=7.2 Hz, 2H), 3.63-3.60 (m, 2H), 3.34-3.31 (m, 2H),3.03-2.97 (m, 2H), 2.37-2.33 (m, 2H), 1.99-1.87 (m, 5H), 1.60-1.50 (m,1H). MS: m/z 364.2 [(M+1)+].

Example G9: (3-Piperidin-1-yl-propyl)-(2-m-tolyl-quinolin-4-yl)-amine

¹H NMR (400 MHz, CDCl₃): δ=8.25 (d, J=8.4 Hz, 2H), 7.68 (s, 1H), 7.70(d, J=7.6 Hz, 1H), 7.57 (t, J=8.0 Hz, 1H), 7.38 (t, J=7.6 Hz, 1H), 7.23(t, J=7.6 Hz, 1H), 7.09 (d, J=7.6 Hz, 1H), 6.57 (s, 1H), 3.56-3.54 (m,2H), 2.91-2.88 (m, 2H), 2.85-2.72 (m, 4H), 2.34 (s, 3H), 2.15-2.13 (m,2H), 1.85-1.81 (m, 4H), 1.60-1.50 (m, 2H). MS: m/z 360.2 [(M+1)+].

Example G10:[2-(4-Dimethylamino-phenyl)-quinolin-4-yl]-(3-piperidin-1-yl-propyl)-amine

¹H NMR (400 MHz, CD₃OD): δ=8.42 (d, J=8.4 Hz, 1H), 8.13 (d, J=8.4 Hz,2H), 7.97 (d, J=8.4 Hz, 1H), 7.89-7.85 (m, 1H), 7.69-7.61 (m, 3H), 7.06(s, 1H), 3.76 (t, J=6.8 Hz, 2H), 3.51-3.49 (m, 2H), 3.25-3.21 (m, 2H),3.20 (s, 6H), 2.93-2.86 (m, 2H), 2.27-2.23 (m, 2H), 1.87-1.73 (m, 5H),1.45-1.42 (m, 1H). MS: m/z 389.2 [(M+1)+].

Example G11: [2-(4-Dimethylamino-phenyl)-quinolin-4-yl]-dimethyl-amine

¹H NMR (400 MHz, CD₃OD): δ=8.45 (d, J=8.4 Hz, 1H), 8.19-8.15 (m, 2H),8.08 (d, J=8.4, 1 Hz, 1H), 7.97 (t, J=8.0 Hz, 1H), 7.78-7.68 (m, 3H),7.15 (s, 1H), 3.62 (s, 6H), 3.34 (s, 6H). MS: m/z 292.1 [(M+1)+].

Example G12:(2-Furan-2-yl-quinolin-4-yl)-(3-piperidin-1-yl-propyl)-amine

¹H NMR (400 MHz, CD₃OD): δ=8.33 (d, J=8.4 Hz, 1H), 7.95-7.91 (m, 2H),7.87-7.83 (m, 1H), 7.74 (d, J=3.6 Hz, 1H), 7.62-7.58 (m, 1H), 7.13 (s,1H), 6.76-6.75 (m, 1H), 3.73 (t, J=6.8 Hz, 2H), 3.51-3.48 (m, 2H),3.23-3.20 (m, 2H), 2.90-2.85 (m, 2H), 2.24-2.17 (m, 2H), 1.88-1.78 (m,2H), 1.75-1.72 (m, 3H), 1.44-1.41 (m, 1H). MS: m/z 336.1 [(M+1)+].

Example G13: (2-Furan-2-yl-quinolin-4-yl)-dimethyl-amine

¹H NMR (400 MHz, CD₃OD): δ=8.39 (d, J=8.4 Hz, 1H), 8.07 (d, J=8.0 Hz,1H), 8.01 (d, J=1.2 Hz, 1H), 7.95-7.91 (m, 1H), 7.76 (d, J=3.6 Hz, 1H),7.68-7.64 (m, 1H), 7.27 (s, 1H), 6.86 (t, J=1.2 Hz, 1H), 3.59 (s, 6H).MS: m/z 239.1 [(M+1)+].

Example G14:(2-Furan-3-yl-quinolin-4-yl)-(3-piperidin-1-yl-propyl)-amine

¹H NMR (400 MHz, CD₃OD): δ=8.63 (s, 1H), 8.35 (d, J=8.4 Hz, 1H), 7.93(d, J=8.4 Hz, 1H), 7.84 (t, J=7.6 Hz, 1H), 7.82 (s, 1H), 7.60 (t, J=7.6Hz, 1H), 7.25 (d, J=1.2 Hz, 1H), 7.03 (s, 1H), 3.73 (t, J=6.8 Hz, 2H),3.51-3.48 (m, 2H), 3.23-3.20 (m, 2H), 2.92-2.86 (m, 2H), 2.23-2.20 (m,2H), 1.87-1.75 (m, 5H), 1.48-1.40 (m, 1H). MS: m/z 336.2 [(M+1)+].

Example G15: (2-Furan-3-yl-quinolin-4-yl)-dimethyl-amine

(2-Furan-3-yl-quinolin-4-yl)-dimethyl-amine

The title compound was prepared using general procedure for3-piperidin-1-yl-propyl)-[2-(2-trifluoromethyl-phenyl)-quinolin-4-yl]-amine.

¹H NMR (400 MHz, CD₃OD): δ=8.49 (s, 1H), 8.28 (d, J=8.4 Hz, 1H), 7.90(d, J=8.4 Hz, 1H), 7.83-7.79 (m, 1H), 7.72 (t, J=1.2, 1H), 7.54 (td,J=8.4, 1.2, 1H), 7.15 (s, 1H), 7.03 (s, 1H), 3.46 (s, 6H). MS: m/z 239.1[(M+1)+].

Example G16:(3-Piperidin-1-yl-propyl)-(2-thiophen-2-yl-quinolin-4-yl)-amine

¹H NMR (400 MHz, CD₃OD): δ=8.35 (d, J=8.4 Hz, 1H), 8.03 (d, J=2.8 Hz,1H), 7.94 (d, J=8.0 Hz, 1H), 7.88-7.85 (m, 2H), 7.84-7.60 (m, 1H), 7.28(dd, J=5.2, 4.0 Hz, 1H), 6.95 (s, 1H), 3.71 (t, J=6.8 Hz, 2H), 3.53-3.48(m, 2H), 3.26-3.20 (m, 2H), 2.91-2.85 (m, 2H), 2.25-2.17 (m, 2H),1.90-1.68 (m, 5H), 1.44-1.41 (m, 1H). MS: m/z 352.1 [(M+1)+].

Example G17: Dimethyl-(2-thiophen-2-yl-quinolin-4-yl)-amine

¹H NMR (400 MHz, CD₃OD): δ=8.29 (d, J=8.4 Hz, 1H), 7.98 (dd, J=3.6, 1.2Hz, 1H), 7.94 (d, J=7.2 Hz, 1H), 7.84-7.80 (m, 2H), 7.57-7.53 (m, 1H),7.26 (t, J=4.8 Hz, 1H), 6.98 (s, 1H), 3.47 (s, 6H). MS: m/z 255.1(M+H+).

Example G18:[2-(1-Methyl-1H-pyrazol-4-yl)-quinolin-4-yl]-(3-piperidin-1-yl-propyl)-amine

¹H NMR (400 MHz, CD₃OD): δ=8.73 (d, J=6.8 Hz, 1H), 8.42-8.40 (m, 2H),8.01-7.94 (m, 2H), 7.73-7.69 (m, 1H), 7.12 (s, 1H), 4.08 (s, 3H), 3.83(t, J=6.8 Hz, 2H), 3.63-3.60 (m, 2H), 3.34-3.30 (m, 2H), 3.03-2.97 (m,2H), 2.36-2.30 (m, 2H), 2.00-1.97 (m, 2H), 1.91-1.83 (m, 3H), 1.58-1.53(m, 1H). MS: m/z 350.2 [(M+1)+].

Example G19:[2-(1-Methyl-1H-pyrazol-4-yl)-quinolin-4-yl]-(3-piperidin-1-yl-propyl)-amine

¹H NMR (400 MHz, CD₃OD): δ=8.50 (s, 1H), 8.26-8.23 (m, 2H), 7.92-7.87(m, 1H), 7.79 (t, J=7.6 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.01 (s, 1H),3.94 (s, 3H), 3.44 (s, 6H). MS: m/z 253.1 [(M+1)+].

Example G20:[2-(1-Methyl-1H-pyrazol-4-yl)-quinolin-4-yl]-(3-piperidin-1-yl-propyl)-amine

¹H NMR (400 MHz, CD₃OD): δ=8.55-8.53 (m, 1H), 8.05-8.01 (m, 1H), 7.96(d, J=8.4 Hz, 1H), 7.80 (t, J=7.6 Hz, 1H), 7.05-7.04 (m, 1H), 3.80 (t,J=6.8 Hz, 2H), 3.62-3.59 (m, 2H), 3.31-3.29 (m, 2H), 3.03-2.97 (m, 2H),2.87 (s, 3H), 2.62 (s, 3H), 2.35-2.29 (m, 2H), 2.00-1.97 (m, 2H),1.92-1.86 (m, 3H), 1.58-1.53 (m, 1H). MS: m/z 381.1 [(M+1)+].

Example G21:[2-(2,4-Dimethyl-thiazol-5-yl)-quinolin-4-yl]-dimethyl-amine

¹H NMR (400 MHz, CD₃OD): δ=8.48 (d, J=8.4, 1H), 8.02-7.94 (m, 2H),7.28-7.23 (m, 1H), 7.04 (s, 1H), 3.62 (s, 6H), 2.90 (s, 3H), 2.62 (s,3H). MS: m/z 284.0 [(M+1)+].

Example G22:(3-Piperidin-1-yl-propyl)-[2-(1H-pyrrol-2-yl)-quinolin-4-yl]-amine

¹H NMR (400 MHz, CD₃OD): δ=8.35 (d, J=8.4 Hz, 1H), 7.98-7.92 (m, 2H),7.66 (t, J=8.0 Hz, 1H), 7.41-7.40 (m, 1H), 7.31 (s, 1H), 7.18 (d, J=1.6Hz, 1H), 6.49-6.47 (m, 1H), 3.83 (t, J=6.8 Hz, 2H), 3.63-3.60 (m, 2H),3.36-3.33 (m, 2H), 3.02-2.98 (m, 2H), 2.34-2.31 (m, 2H), 1.97-1.85 (m,5H), 1.59-1.51 (m, 1H). MS: m/z 335.2 [(M+1)+].

Example G23: Dimethyl-[2-(1H-pyrrol-2-yl)-quinolin-4-yl]-amine

¹H NMR (400 MHz, CD₃OD): δ=8.19 (d, J=8.4 Hz, 1H), 7.86 (d, J=8.4 Hz,1H), 7.77-7.73 (m, 1H), 7.49-7.45 (m, 1H), 7.25-7.24 (m, 1H), 7.15 (t,J=1.6 Hz, 1H), 7.02 (s, 1H), 6.34 (dd, J=3.6, 2.8 Hz, 1H), 3.41 (s, 6H).MS: m/z 238.2 [(M+1)+].

Example G24:[2-(4-methoxy-phenyl)-6-methyl-quinolin-4-yl]-(3-piperidin-1-yl-propyl)-amine

¹H NMR (400 MHz, CD₃OD): δ=8.30 (s, 1H), 8.02-7.99 (m, 2H), 7.94 (d,J=8.4 Hz, 1H), 7.84 (dd, J=8.8, 1.6 Hz, 1H), 7.23 (d, J=8.8 Hz, 2H),7.05 (s, 1H), 3.96 (s, 3H), 3.83 (t, J=7.2 Hz, 2H), 3.63-3.60 (m, 2H),3.43-3.30 (m, 2H), 3.02-2.99 (m, 2H), 2.63 (s, 3H), 2.35-2.31 (m, 2H),2.00-1.85 (m, 5H), 1.60-1.49 (m, 1H). MS: m/z 390.2 [(M+1)+].

Example G25:[6-Methoxy-2-(4-methoxy-phenyl)-quinolin-4-yl]-(3-piperidin-1-yl-propyl)-amine

¹H NMR (400 MHz, CD₃OD): δ=7.88-7.84 (m, 3H), 7.77 (d, J=2.4 Hz, 1H),7.48 (dd, J=9.2, 2.8 Hz, 1H), 7.10 (d, J=8.8 Hz, 2H), 6.91 (s, 1H), 3.93(s, 3H), 3.82 (s, 3H), 3.71 (t, J=7.2 Hz, 2H), 3.50-3.48 (m, 2H),3.22-3.19 (m, 2H), 2.90=2.84 (m, 2H), 2.26-2.20 (m, 2H), 1.87-1.73 (m,5H), 1.46-1.40 (m, 1H). MS: m/z 406.2 [(M+1)+].

Example G26:[7-Methoxy-2-(4-methoxy-phenyl)-quinolin-4-yl]-(3-piperidin-1-yl-propyl)-amine

¹H NMR (400 MHz, CD₃OD): δ=8.37 (d, J=9.6 Hz, 1H), 8.00 (dd, J=12.0, 3.2Hz, 2H), 7.44-7.42 (m, 1H), 7.34-7.31 (m, 1H), 7.23 (dd, J=12.0, 3.2 Hz,2H), 6.98 (s, 1H), 4.03 (s, 3H), 3.96 (s, 3H), 3.81 (t, J=7.2 Hz, 2H),3.62-3.59 (m, 2H), 3.43-3.30 (m, 2H), 3.03-2.97 (m, 2H), 2.35-2.27 (m,2H), 2.01-1.82 (m, 5H), 1.60-1.52 (m, 1H). MS: m/z 406.2 [(M+1)+].

Example G27:[6-Chloro-2-(4-methoxy-phenyl)-quinolin-4-yl]-(3-piperidin-1-yl-propyl)-amine

¹H NMR (300 MHz, CDCl₃): δ=8.08-8.00 (m, 4H), 7.55 (dd, J=9.0, 1.8 Hz,1H), 7.02 (d, J=8.7 Hz, 2H), 6.72 (s, 1H), 3.89 (s, 3H), 3.49-3.47 (m,2H), 2.67-2.55 (m, 5H), 2.06-1.99 (m, 3H), 1.90-1.82 (m, 6H). MS: m/z410.1 [(M+1)+].

Example G28:[2-(4-Methoxy-phenyl)-6-trifluoromethyl-quinolin-4-yl]-(3-piperidin-1-yl-propyl)-amine

¹H NMR (400 MHz, CD₃OD): δ=8.95 (s, 1H), 8.23-8.20 (m, 2H), 8.07 (d,J=8.0 Hz, 2H), 7.25 (dd, J=6.8, 2.0 Hz, 2H), 7.19 (s, 1H), 3.97 (s, 3H),3.87 (t, J=7.2 Hz, 2H), 3.63-3.60 (m, 2H), 3.53-3.31 (m, 2H), 3.03-2.96(m, 2H), 2.37-2.33 (m, 2H), 1.96-1.87 (m, 5H), 1.60-1.51 (m, 1H). MS:m/z 444.2 [(M+1)+].

Example G29:[2-(4-Methoxy-phenyl)-6-nitro-quinolin-4-yl]-(3-piperidin-1-yl-propyl)-amine

¹H NMR (400 MHz, CD₃OD): δ=9.41 (s, 1H), 8.60 (dd, J=9.2, 2.0 Hz, 1H),8.08 (d, J=9.6 Hz, 1H), 7.96 (d, J=8.8 Hz, 2H), 7.13 (d, J=7.2 Hz, 2H),7.08 (s, 1H), 3.84 (s, 3H), 3.80-3.74 (m, 2H), 3.56-3.47 (m, 2H),3.21-3.20 (m, 2H), 2.90-2.84 (m, 2H), 2.25-2.23 (m, 2H), 1.87-1.74 (m,5H), 1.50-1.41 (m, 1H). MS: m/z 421.2 [(M+1)+].

Example G30:[6-Fluoro-2-(4-methoxy-phenyl)-quinolin-4-yl]-(3-piperidin-1-yl-propyl)-amine

¹H NMR (400 MHz, CD₃OD): δ=8.29 (dd, J=9.6, 2.8 Hz, 1H), 8.11 (dd,J=9.6, 4.8 Hz, 1H), 8.03 (dd, J=6.4, 2.4 Hz, 2H), 7.86-7.81 (m, 1H),7.24 (d, J=8.0 Hz, 2H), 7.10 (s, 1H), 3.96 (s, 3H), 3.84 (t, J=7.2 Hz,2H), 3.63-3.60 (m, 2H), 3.43-3.31 (m, 2H), 3.03-2.96 (m, 2H), 2.35-2.31(m, 2H), 2.00-1.86 (m, 5H), 1.60-1.53 (m, 1H). MS: m/z 394.2 [(M+1)+].

Example G31:[2-(4-Methoxy-phenyl)-6-trifluoromethoxy-quinolin-4-yl]-(3-piperidin-1-yl-propyl)-amine

¹H NMR (400 MHz, CD₃OD): δ=8.50 (s, 1H), 8.19-8.16 (m, 1H), 8.07-8.04(m, 2H), 7.94 (dd, J=6.8, 1.6 Hz, 1H), 7.27-7.23 (m, 2H), 7.15 (s, 1H),3.99 (s, 3H), 3.85 (t, J=6.8 Hz, 2H), 3.63-3.60 (m, 2H), 3.37-3.31 (m,2H), 3.03-2.96 (m, 2H), 2.38-2.31 (m, 2H), 1.99-1.87 (m, 5H), 1.32-1.30(m, 1H). MS: m/z 460.2 [(M+1)+].

Example G32:3-[2-(2-Trifluoromethyl-phenyl)-quinolin-4-ylamino]-benzonitrile

¹H NMR (400 MHz, DMSO-d6): δ=9.35 (s, 1H), 8.40 (d, J=8.0 Hz, 1H), 7.95(d, J=8.4 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.81-7.52 (m, 9H), 7.09 (s,1H). MS: m/z 390.1 [(M+1)+].

Example G33: Phenyl-[2-(2-trifluoromethyl-phenyl)-quinolin-4-yl]-amine

¹H NMR (400 MHz, DMSO-d6): δ=9.13 (s, 1H), 8.45 (d, J=8.0 Hz, 1H), 7.90(d, J=8.0 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.77-7.71 (m, 2H), 7.66-7.57(m, 3H), 7.43-7.36 (m, 4H), 7.15-7.12 (m, 1H), 6.93 (s, 1H). MS: m/z365.1 [(M+1)+].

Example G34:(4-Fluoro-phenyl)-[2-(2-trifluoromethyl-phenyl)-quinolin-4-yl]-amine

¹H NMR (400 MHz, DMSO-d6): δ=9.10 (s, 1H), 8.43 (d, J=8.4 Hz, 1H), 7.89(d, J=8.4 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.77-7.71 (m, 2H), 7.66-7.56(m, 3H), 7.40-7.37 (m, 2H), 7.27-7.23 (m, 2H), 6.78 (s, 1H). MS: m/z383.1 [(M+1)+].

Example G35: [2-(4-Methoxy-phenyl)-quinolin-4-yl]-phenyl-amine

¹H NMR (400 MHz, DMSO-d6): δ=8.99 (s, 1H), 8.37 (d, J=8.0 Hz, 1H),7.98-7.91 (m, 3H), 7.70 (t, J=8.0 Hz, J=1.2 Hz, 1H), 7.52-7.41 (m, 6H),7.18-7.06 (m, 1H), 7.02 (d, J=2.8 Hz, 2H), 3.80 (s, 3H). MS: m/z 327.1[(M+1)+].

Example G36:[2-(4-Methoxy-phenyl)-quinolin-4-yl]-(2-trifluoromethyl-phenyl)-amine

¹H NMR (400 MHz, CD₃OD): δ=8.46 (d, J=8.4 Hz, 1H), 8.02-7.90 (m, 3H),7.82 (t, J=8.0 Hz, 1H), 7.75-7.65 (m, 2H), 7.63-7.59 (m, 3H), 7.02 (d,J=8.8 Hz, 2H), 6.29 (s, 1H), 3.78 (s, 3H). MS: m/z 395.1 [(M+1)+].

Example G37:[2-(4-Methoxy-phenyl)-quinolin-4-yl]-(3-trifluoromethyl-phenyl)-amine

¹H NMR (400 MHz, DMSO-d6): δ=9.26 (s, 1H), 8.34 (d, J=8.0 Hz, 1H), 8.03(d, J=8.8 Hz, 2H), 7.97 (d, J=8.4 Hz, 1H), 7.79-7.71 (m, 3H), 7.65 (t,J=8.0 Hz, 1H), 7.59 (s, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.43 (d, J=7.6 Hz,1H), 7.05 (d, J=9.2 Hz, 2H), 3.82 (s, 3H). MS: m/z 395.1 [(M+1)+].

Example G38: 3-[2-(4-Methoxy-phenyl)-quinolin-4-ylamino]-benzonitrile

¹H NMR (400 MHz, DMSO-d6): δ=9.20 (s, 1H), 8.31-8.29 (m, 1H), 8.06-8.03(m, 2H), 7.98-7.95 (m, 1H), 7.79-7.71 (m, 3H), 7.64-7.52 (m, 4H), 7.05(d, J=11.6 Hz, 2H), 3.83 (s, 3H). MS: m/z 352.1 [(M+1)+].

Example G63: [2-(4-Methoxy-phenyl)-quinolin-4-yl]-pyridin-2-yl-amine

To a mixture of 4-chloro-2-(4-methoxy-phenyl)-quinoline (100 mg, 0.37mmol), Pd₂(dba)₃ (34 mg, 0.04 mmol), xantphos (35 mg, 0.07 mmol), Cs₂CO₃(241 mg, 0.74 mmol) in dioxane (5 mL) was added pyridin-2-ylamine (35mg, 0.37 mmol) under N₂ atmosphere. The reaction mixture was stirred at100° C. for 3 hrs. The mixture was concentrated under reduced pressureand the residue was partitioned between water (20 mL) and DCM (20 mL).It was extracted with DCM (20 mL×3). The combined organic phase waswashed with brine, and dried over NaSO₄. After filtration, the solventwas removed, and the residue was purified by prep-HPLC to give[2-(4-methoxy-phenyl)-quinolin-4-yl]-pyridin-2-yl-amine (40 mg, yield:33%) as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ=9.44 (s, 1H), 8.98(s, 1H), 8.47 (d, J=8.0 Hz, 1H), 8.39-8.38 (m, 1H), 8.12 (d, J=8.8 Hz,2H), 7.97 (d, J=8.0 Hz, 1H), 7.79-7.75 (m, 1H), 7.72 (t, J=7.2 Hz, 1H),7.55 (t, J=7.2 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.11-7.09 (m, 2H),7.00-6.99 (m, 1H), 3.84 (s, 3H). MS: m/z 328.1 [(M+1)+].

Example G64:(4-Chloro-benzyl)-[2-(4-methoxy-phenyl)-quinolin-4-yl]-amine

To a mixture of 4-chloro-2-(4-methoxy-phenyl)-quinoline (150 mg, 0.560mmol) in DMA (2.5 mL), was added t-BuOK (3.7 mg, 0.034 mmol) and4-chloro-benzylamine (316 mg, 2.240 mmol). The resulting mixture wasstirred for 4 hrs at 180° C. by microwave. The mixture was partitionedbetween water (30 mL) and EA (30 mL), extracted with EA (30 mL×2). Thecombined organic phase was washed with brine (80 mL×2) and dried overNaSO₄. After filtration, the solvent was removed, and the residue waspurified by silica gel column chromatography (PE/EA=2/1) to give(4-chloro-benzyl)-[2-(4-methoxy-phenyl)-quinolin-4-yl]-amine (34 mg,yield: 16%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ=8.62 (d, J=8.0Hz, 1H), 8.57 (d, J=6.8 Hz, 1H), 7.83 (d, J=8.0 Hz, 2H), 7.40-7.34 (m,3H), 7.30-7.20 (m, 3H), 6.94 (d, J=8.0 Hz, 2H), 6.31 (s, 1H), 4.72 (d,J=5.2 Hz, 2H), 3.79 (s, 3H). MS: m/z 375.1 [(M+1)+]

In some embodiments, compounds described herein are prepared as shown inScheme 3.

The synthesis of compound XV can be accomplished by the reactionsillustrated in Scheme 3. Treatment compound XII in an inert organicsolvent such as THF, DMF, DMA containing an organic base such astriethylamine, or strong base such as potassium t-butoxide, sodiumhydride or potassium hydride with an alcohol or amine compound offormula HZR₂ produces compounds of formula XIII. The reaction ispreferably carried out at temperatures between 25° C. and 150° C. Thepredominate isomer produced in this reaction is the C4 addition on thearomatic ring. Crystallization of the product of this reaction allowsfor the isolation of only the C4 isomer. Suzuki coupling of compoundXIII with an aromatic boronic acid XIV employing standard Suzukicoupling conditions using a palladium zero species such as Pd(PPh₃)₄,with aqueous potassium carbonate or sodium carbonate in an inert solventsuch as acetonitrile or toluene produces Compound XV. The reaction ispreferably carried out at temperatures between 25° C. and 150° C.

Preparation of Compounds of Structure XIII

General Procedure H Example H1: Preparation of2-chloro-N-(3-(piperidin-1-yl)propyl)quinolin-4-amine

To a mixture of 2,4-dichloroquinolne (5 g),3-(piperidin-1-yl)propan-1-amine (3.5 g), potassium carbonate (6.96 g)was added DMA (100 ml). The reaction was heated for 20 hours, cooled andthe solvent removed under vacuum. The residue was extracted withDCM/water and dried over sodium sulfate. The resulting solid waspurified with silica gel eluted with 70% DCM/30% MeOH. The resultingsolid was recrystallized from MeOH, to afford of2-chloro-N-(3-(piperidin-1-yl)propyl)quinolin-4-amine (4 g, yield: 63%)as a white/tan solid, MS (EI): m/z 304 [(M+1)+].

Preparation of Compounds of Structure XV

General Procedure I Example I1: Preparation ofN,N-diethyl-4-(4-((3-(piperidin-1-yl)propyl)amino)quinolin-2-yl)benzamide

To a mixture of 2-chloro-N-(3-(piperidin-1-yl)propyl)quinolin-4-amine(1.72 g), 4-diethylaminoboronic acid (1.87 g) was added 10 ml of 2Msodium carbonate, 10 ml of toluene and 10 ml of EtOH. The reactionmixture was purged with nitrogen and then Pd (500 mg) was added and thereaction was heated to 85° C. for 6 hours. The reaction mixture wascooled and extracted with EtOAc/water. The organic layer was dried oversodium sulfate and the solvent removed under vacuum. The residue waspurified using silica gel and eluted with a gradient of 70% DCM/30% MeOHto 30% DCM/70% MeOH, to affordN,N-diethyl-4-(4-((3-(piperidin-1-yl)propyl)amino)quinolin-2-yl)benzamide(1.1 g, yield: 33%) as a white/tan solid, MS (EI): m/z 445 [(M+1)+].

Example 2: LMPTP Primary Screening Protocol

This assay attempts to identify inhibitors of the LMPTP-A (Low MolecularWeight Protein Tyrosine Phosphatase-A) enzyme. It is run in 1536-wellformat and is measured via fluorescence intensity.

A listing of materials is provided:

-   -   Item, source, catalog no.    -   LMPTP-A Enzyme Stock Solution (4.22 mg/ml or 206.8 μM), SBMRI        Protein Facility,    -   N/A    -   OMFP, Sigma, M2629-100 MG    -   Bis-Tris pH 6.0, Fisher Sci, BP301-100    -   Triton-X 100, Sigma, T9284    -   DTT, Sigma, D9779    -   Mol. Grade Water, Mediatech, Inc., 46-000-CM    -   1536-well black High base opaque bottom plate, Nexus Biosystems,        00019120

Final assay conditions are:

-   -   0.625 nM LMPTP-A Enzyme    -   40 μM OMFP    -   50 mM Bis-Tris pH 6.0    -   1 mM DTT    -   0.01% Triton-X 100    -   20 μM test compound    -   3% DMSO (2% from substrate and 1% from compounds)    -   6 μL reaction volume    -   50 minutes incubation at room temp

Assay Procedure

-   -   1. Prepare Reagents as described in section F. Recipe.    -   2. Using LabCyte Echo, transfer 60 nL from 2 mM test compound        source plate into assay plate Col. 5-48 (final concentration of        test compounds is 20 μM). 60 nL of DMSO should be transferred to        col. 1-4 for positive and negative control wells.    -   3. Spin plates at 1000 rpm for 1 minute in centrifuge.    -   4. Using the Beckman Coulter Bioraptr, add 3 μL/well of control        buffer to columns 1 and 2.    -   5. Using the Bioraptr, add 3 μL/well of enzyme solution to col.        3-48.    -   6. Using the Bioraptr, add 3 μL/well of substrate solution to        col. 1-48.    -   7. Spin plates at 1000 rpm for 1 minute in centrifuge.    -   8. Incubate plates in the dark at room temperature for 50        minutes.    -   9. Read plates on PerkinElmer Viewlux using a FI protocol.

Example 3

The following compounds were prepared using Procedures A-I of Example 1described above, and the IC₅₀ values were obtained using the method ofExample 2. IC₅₀ values are categorized according to the below scale.

-   -   A: IC₅₀>200 nM−<800 nM    -   B: IC₅₀>801 nM−<5000 nM    -   C: IC₅₀>5001 nM

TABLE A MW (EI) IC50 Compound Name [(M + 1)+] (nM) D12-(4-methoxyphenyl)-N-(3-(piperidin-1- 376 B yl)propyl)quinolin-4-amine:D2 N,N-dimethyl-2-(2- 317 B (trifluoromethyl)phenyl)quinolin-4-amine G1(3-piperidin-1-yl-propyl)-[2-(2-trifluoromethyl- 414 Bphenyl)-quinolin-4-yl]-amine G2 (3-piperidylpropyl){2-[2- 430 A(trifluoromethoxy)phenyl](4-quinolyl)}amine G3(3-Piperidin-1-yl-propyl)-[2-(3-trifluoromethoxy- 430 Bphenyl)-quinolin-4-yl]-amine G4(3-Piperidin-1-yl-propyl)-[2-(4-trifluoromethoxy- 430 Bphenyl)-quinolin-4-yl]-amine G5 N,N-dimethyl-2-(4- 317 B(trifluoromethoxy)phenyl)quinolin-4-amine G6[2-(2-fluorophenyl)(4-quinolyl)](3- 364 B piperidylpropyl)amine G7[2-(3-Fluoro-phenyl)-quinolin-4-yl]-(3-piperidin- 364 B1-yl-propyl)-amine364 G8[2-(4-Fluoro-phenyl)-quinolin-4-yl]-(3-piperidin-1- 364 Byl-propyl)-amine G9 (3-Piperidin-1-yl-propyl)-(2-m-tolyl-quinolin-4- 360B yl)-amine G10 [2-(4-Dimethylamino-phenyl)-quinolin-4-yl]-(3- 389 Bpiperidin-1-yl-propyl)-amine G11[2-(4-Dimethylamino-phenyl)-quinolin-4-yl]- 292 C dimethyl-amine G12(2-Furan-2-yl-quinolin-4-yl)-(3-piperidin-1-yl- 336 B propyl)-amine G13(2-Furan-2-yl-quinolin-4-yl)-dimethyl-amine: 239 C G14(2-Furan-3-yl-quinolin-4-yl)-(3-piperidin-1-yl- 336 B propyl)-amine G15(2-Furan-3-yl-quinolin-4-yl)-dimethyl-amine 239 C G16(3-Piperidin-1-yl-propyl)-(2-thiophen-2-yl- 352 B quinolin-4-yl)-amineG17 Dimethyl-(2-thiophen-2-yl-quinolin-4-yl)-amine 255 C G18[2-(1-methylpyrazol-3-yl)(4-quinolyl)](3- 350 C piperidylpropyl)amineG19 Dimethyl[2-(1-methylpyrazol-4-yl)(4- 253 C quinolyl)]amine G20[2-(2,4-dimethyl(1,3-thiazol-5-yl))(4-quinolyl)](3- 381 Bpiperidylpropyl)amine G21 [2-(2,4-Dimethyl-thiazol-5-yl)-quinolin-4-yl]-284 C dimethyl-amine G22 (3-Piperidin-1-yl-propyl)-[2-(1H-pyrrol-2-yl)-335 B quinolin-4-yl]-amine G23Dimethyl-[2-(1H-pyrrol-2-yl)-quinolin-4-yl]-amine 238 C G24[2-(4-methoxy-phenyl)-6-methyl-quinolin-4-yl]-(3- 390 Cpiperidin-1-yl-propyl)-amine G25[6-Methoxy-2-(4-methoxy-phenyl)-quinolin-4- 406 Cyl]-(3-piperidin-1-yl-propyl)-amine G26[7-Methoxy-2-(4-methoxy-phenyl)-quinolin-4- 406 Cyl]-(3-piperidin-1-yl-propyl)-amine G27[6-Chloro-2-(4-methoxy-phenyl)-quinolin-4- 410 Cyl]-(3-piperidin-1-yl-propyl)-amine G28[2-(4-Methoxy-phenyl)-6-trifluoromethyl-quinolin- 444 C4-yl]-(3-piperidin-1-yl-propyl)-amine G29[2-(4-Methoxy-phenyl)-6-nitro-quinolin-4-yl]-(3- 421 Cpiperidin-1-yl-propyl)-amine G30[6-Fluoro-2-(4-methoxy-phenyl)-quinolin-4-yl]-(3- 394 Bpiperidin-1-yl-propyl)-amine G31[2-(4-Methoxy-phenyl)-6-trifluoromethoxy-quinolin- 460 C4-yl]-(3-piperidin-1-yl-propyl)-amine G323-[2-(2-Trifluoromethyl-phenyl)-quinolin-4- 390 B ylamino]-benzonitrileG33 Phenyl-[2-(2-trifluoromethyl-phenyl)-quinolin-4- 365 C yl]-amine G34(4-Fluoro-phenyl)-[2-(2-trifluoromethyl-phenyl)- 383 Bquinolin-4-yl]-amine G35 [2-(4-Methoxy-phenyl)-quinolin-4-yl]-phenyl-327 B amine G36 [2-(4-Methoxy-phenyl)-quinolin-4-yl]-(2- 395 Ctrifluoromethyl-phenyl)-amine G37[2-(4-Methoxy-phenyl)-quinolin-4-yl]-(3- 395 Ctrifluoromethyl-phenyl)-amine G383-[2-(4-Methoxy-phenyl)-quinolin-4-ylamino]- 352 A benzonitrile G39(4-fluorophenyl)[2-(4-methoxyphenyl)(4- 345 B quinolyl)]amine G40(4-chlorophenyl)[2-(4-methoxyphenyl)(4- 361 B quinolyl)]amine G41(4-bromophenyl)[2-(4-methoxyphenyl)(4- 406 B quinolyl)]amine G42[2-(4-methoxyphenyl)(4-quinolyl)][4- 395 B (trifluoromethyl)phenyl]amineG43 [2-(4-methoxyphenyl)(4-quinolyl)](4- 341 B methylphenyl)amine G44[2-(4-methoxyphenyl)(4-quinolyl)][4- 385 B (methylethoxy)phenyl]amineG45 ethyl 4-{[2-(4-methoxyphenyl)-4- 399 C quinolyl]amino}benzoate G462-(4-methoxyphenyl)(4-quinolyl)](1- 331 B methylpyrazol-3-yl)amine G474-{[2-(4-methoxyphenyl)-4- 352 A quinolyl]amino}benzenecarbonitrile G48(6-methoxy(3-pyridyl))[2-(4-methoxyphenyl)(4- 358 A quinolyl)]amine G49(3-chloro-4-fluorophenyl)[2-(4-methoxyphenyl)(4- 379 B quinolyl)]amineG50 [2-(4-methoxyphenyl)(4-quinolyl)][3- 410 A(pyrrolidinylmethyl)phenyl]amine G51 2-(4-methoxyphenyl)(4-quinolyl)][3-410 A (pyrrolidinylmethyl)phenyl]amine G52[2-(4-methoxyphenyl)(4-quinolyl)][4-(morpholin- 426 B4-ylmethyl)phenyl]amine G53 [2-(4-methoxyphenyl)(4-quinolyl)][3-(4- 424B piperidylmethyl)phenyl]amine G54 [2-(4-methoxyphenyl)(4-quinolyl)][3-424 B (piperidylmethyl)phenyl]amine G55[2-(4-methoxyphenyl)(4-quinolyl)][3-(morpholin- 426 A4-ylmethyl)phenyl]amine G56 [2-(4-methoxyphenyl)(4-quinolyl)][3-(1,4-426 A thiazaperhydroin-4-ylmethyl)phenyl]amine G57[2-(4-methoxyphenyl)(4-quinolyl)]{3-[(4- 453 A methyl(1,4-diazaperhydroepinyl))methyl]phenyl}amine G58[(3-{[2-(4-methoxyphenyl)(4- 384 Aquinolyl)]amino}phenyl)methyl]dimethylamine G59[2-(4-methoxyphenyl)(4-quinolyl)][3- 425 B(piperazinylmethyl)phenyl]amine G60[2-(4-methoxyphenyl)(4-quinolyl)]{3-[(4- 439 Bmethylpiperazinyl)methyl]phenyl}amine G61(3-Diethylaminomethyl-phenyl)-[2-(4-methoxy- 412 Bphenyl)-quinolin-4-yl]-amine G62 4-[(3-{[2-(4-methoxyphenyl)-4- 474 Bquinolyl]amino}phenyl)methyl]-1,4- thiazaperhydroine-1,1-dione G63[2-(4-methoxyphenyl)(4-quinolyl)]-2-pyridylamine 328 B G64[2-(4-methoxyphenyl)(4-quinolyl)]-2-pyridylamine 328 B G65[2-(4-methoxyphenyl)(4-quinolyl)]-4-pyridylamine 328 B G66[2-(4-methoxyphenyl)(4-quinolyl)]pyrimidin-5- 329 B ylamine G67[2-(4-methoxyphenyl)(4-quinolyl)](6-methyl(2- 342 B pyridyl))amine G68[2-(4-methoxyphenyl)(4-quinolyl)]-2- 378 B quinolylamine G692-(4-methoxyphenyl)(4-quinolyl)]-8-quinolylamine 378 C G70[2-(4-methoxyphenyl)(4-quinolyl)]pyrimidin-4- 329 B ylamine G71[2-(4-methoxyphenyl)(4-quinolyl)]pyridazin-4- 329 B ylamine G72[2-(4-methoxyphenyl)(4-quinolyl)]pyrimidin-2- 329 B ylamine G73[2-(4-methoxyphenyl)(4-quinolyl)](6- 343 B methylpyrazin-2-yl)amine G74[(4-chlorophenyl)methyl][2-(4-methoxyphenyl)(4- 375 B quinolyl)]amineG75 [2-(4-methoxyphenyl)(4-quinolyl)]benzylamine 341 B G76[2-(4-methoxyphenyl)(4- 355 B quinolyl)](phenylethyl)amine G77[2-(4-methoxyphenyl)(4-quinolyl)][(2- 371 B methoxyphenyl)methyl]amineG78 [2-(4-methoxyphenyl)(4-quinolyl)][(3- 371 Bmethoxyphenyl)methyl]amine G79 [2-(4-methoxyphenyl)(4-quinolyl)][(4- 371B methoxyphenyl)methyl]amine G80 [2-(4-methoxyphenyl)(4-quinolyl)]{[2-409 B (trifluoromethyl)phenyl]methyl}amine G81[2-(4-methoxyphenyl)(4-quinolyl)]{[4- 409 B(trifluoromethyl)phenyl]methyl}amine G82 3-({[2-(4-methoxyphenyl)-4- 366B quinolyl]amino}methyl)benzenecarbonitrile G83[2-(4-methoxyphenyl)(4-quinolyl)](2- 355 B phenylethyl)amine G84[2-(4-chlorophenyl)ethyl][2-(4- 389 B methoxyphenyl)(4-quinolyl)]amineG85 [2-(4-methoxyphenyl)(4-quinolyl)][2-(4- 385 Bmethoxyphenyl)ethyl]amine G86 [2-(4-methoxyphenyl)(4-quinolyl)]{2-[4-423 B (trifluoromethyl)phenyl]ethyl}amine G87[2-(4-fluorophenyl)ethyl][2-(4- 373 B methoxyphenyl)(4-quinolyl)]amineI1 N,N-diethyl-4-(4-((3-(piperidin-1- 445 Ayl)propyl)amino)quinolin-2-yl)benzamide I22-(4-{[3-(pyrrolidinylmethyl)phenyl]amino}-2- 405 Bquinolyl)benzenecarbonitrile I34-(4-{[3-(4-piperidylmethyl)phenyl]amino}-2- 437 B quinolyl)benzamide I44-[4-({3-[(dimethylamino)methyl]phenyl}amino)- 397 C2-quinolyl]benzamide I5 4-(4-{[3-(pyrrolidinylmethyl)phenyl]amino}-2-423 C quinolyl)benzamide I6 4-(4-{[4-(piperidylmethyl)phenyl]amino}-2-437 C quinolyl)benzamide I7[2-(4-chloro-2-fluorophenyl)(4-quinolyl)][3-(4- 446 Bpiperidylmethyl)phenyl]amine I8[2-(4-chloro-2-fluorophenyl)(4-quinolyl)][4- 446 B(piperidylmethyl)phenyl]amine I9 [(3-{[2-(4-chloro-2-fluorophenyl)(4-406 B quinolyl)]amino}phenyl)methyl]dimethylamine I10[2-(4-chloro-2-fluorophenyl)(4-quinolyl)][3- 432 B(pyrrolidinylmethyl)phenyl]amine I11 [2-(3-chlorophenyl)(4-quinolyl)][4-428 B (piperidylmethyl)phenyl]amine I12[2-(3-chlorophenyl)(4-quinolyl)][3- 414 B(pyrrolidinylmethyl)phenyl]amine I13(5-[(dimethylamino)methyl]-3-{[2-(3- 418 Bchlorophenyl)(4-quinolyl)]amino}phenyl)methan- 1-ol I14(3-{[2-(3-chlorophenyl)(4- 374 B quinolyl)]amino}phenyl)dimethylamineI15 [2-(3-chlorophenyl)(4-quinolyl)][2-(1- 366 Bmethylpyrrolidin-2-yl)ethyl]amine I16 [(4-{[2-(3-chlorophenyl)(4- 388 Bquinolyl)]amino}phenyl)methyl]dimethylamine I17[2-(3-chlorophenyl)(4-quinolyl)](3-{[1-benzyl(4- 519 Bpiperidyl)]methyl}phenyl)amine I18[2-(3-chlorophenyl)(4-quinolyl)]{3-[(1-methyl(4- 442 Bpiperidyl))methyl]phenyl}amine I19[2-(3-chlorophenyl)(4-quinolyl)][3-(4- 428 Bpiperidylmethyl)phenyl]amine I20 [2-(3-chlorophenyl)(4-quinolyl)][3-(4-428 B piperidylmethyl)phenyl]amine I21[2-(3-chlorophenyl)(4-quinolyl)][2-(4- 428 Bpiperidylmethyl)phenyl]amine I22 [(3-{[2-(3-chlorophenyl)(4- 388 Aquinolyl)]amino}phenyl)methyl]dimethylamine I23[2-(4-methoxyphenyl)(4-quinolyl)][4- 424 B (piperidylmethyl)phenyl]amineI24 [2-(4-methoxyphenyl)(4-quinolyl)][2-(1- 362 Bmethylpyrrolidin-2-yl)ethyl]amine I25 (3-{[2-(4-methoxyphenyl)(4- 370 Bquinolyl)]amino}phenyl)dimethylamine I26 [(4-{[2-(4-methoxyphenyl)(4-384 B quinolyl)]amino}phenyl)methyl]dimethylamine I27[2-(4-methoxyphenyl)(4-quinolyl)][3-(2H-1,2,3,4- 409 Btetraazol-5-ylmethyl)phenyl]amine I28 4-[(3-{[2-(4-methoxyphenyl)(4- 502B quinolyl)]amino}phenyl)methyl]-1- (methylsulfonyl)piperidine I291-acetyl-4-[(3-{[2-(4-methoxyphenyl)(4- 466 Aquinolyl)]amino}phenyl)methyl]piperidine I30{3-[(1-ethyl(4-piperidyl))methyl]phenyl}[2-(4- 452 Amethoxyphenyl)(4-quinolyl)]amine I31[2-(4-methoxyphenyl)(4-quinolyl)]{3-[(1- 438 Amethyl(4-piperidyl))methyl]phenyl}amine I32[2-(4-methoxyphenyl)(4-quinolyl)][4-(4- 424 Bpiperidylmethyl)phenyl]amine I33{4-[(1-ethyl(4-piperidyl))methyl]phenyl}[2-(4- 452 Bmethoxyphenyl)(4-quinolyl)]amine I341-acetyl-4-[(4-{[2-(4-methoxyphenyl)(4- 466 Bquinolyl)]amino}phenyl)methyl]piperidine I354-[(4-{[2-(4-methoxyphenyl)(4- 502 B quinolyl)]amino}phenyl)methyl]-1-(methylsulfonyl)piperidine I36 2-(3-{[2-(4-methoxyphenyl)-4- 366 Bquinolyl]amino}phenyl)ethanenitrile I37[2-(4-methoxyphenyl)(4-quinolyl)]{2-[(1- 438 Cmethyl(4-piperidyl))methyl]phenyl}amine I38[2-(4-methoxyphenyl)(4-quinolyl)][2-(4- 424 Cpiperidylmethyl)phenyl]amine I39 [(3-{[2-(4-methoxyphenyl)(4- 384 Bquinolyl)]amino}phenyl)methyl]dimethylamine I40{2-[2,5-bis(trifluoromethyl)phenyl](4-quinolyl)}(3- 620 C{[1-benzyl(4-piperidyl)1methyl}phenyl)amine I41{2-[2,5-bis(trifluoromethyl)phenyl](4-quinolyl)}[3- 530 B(4-piperidylmethyl)phenyl]amine I42{[3-({2-[3,5-bis(trifluoromethyl)phenyl](4- 490 Cquinolyl)}amino)phenyl]methyl}dimethylamine I43{2-[3,5-bis(trifluoromethyl)phenyl](4-quinolyl)}[4- 530 C(piperidylmethyl)phenyl]amine I44{2-[3,5-bis(trifluoromethyl)phenyl](4-quinolyl)}[3- 516 C(pyrrolidinylmethyl)phenyl]amine I45(5-[(dimethylamino)methyl]-3-{[2-(3- 418 Bchlorophenyl)(4-quinolyl)]amino}phenyl)methan-1-ol I46{2-[3,5-bis(trifluoromethyl)phenyl](4-quinolyl)}[2- 468 C(1-methylpyrrolidin-2-yl)ethyl]amine I47{[4-({2-[3,5-bis(trifluoromethyl)phenyl](4- 490 Cquinolyl)}amino)phenyl]methyl}dimethylamine I48{2-[(1,1-dimethyl(4-piperidyl))methyl]phenyl}{2- 559 C[3,5-bis(trifluoromethyl)phenyl](4-quinolyl)}amine I49{2-[3,5-bis(trifluoromethyl)phenyl](4-quinolyl)}[2- 530 C(4-piperidylmethyl)phenyl]amine I50{2-[3,5-bis(trifluoromethyl)phenyl](4-quinolyl)}(3- 620 C{[1-benzyl(4-piperidyl)]methyl}phenyl)amine I51{3-[(1,1-dimethyl(4-piperidyl))methyl]phenyl}{2- 559 C[3,5-bis(trifluoromethyl)phenyl](4-quinolyl)}amine I52{2-[3,5-bis(trifluoromethyl)phenyl](4-quinolyl)}[3- 530 C(4-piperidylmethyl)phenyl]amine I53{2-[2,4-bis(trifluoromethyl)phenyl](4-quinolyl)}[2- 468 C(1-methylpyrrolidin-2-yl)ethyl]amine I54{[4-({2-[2,4-bis(trifluoromethyl)phenyl](4- 490 Cquinolyl)}amino)phenyl]methyl}dimethylamine I55{2-[2,4-bis(trifluoromethyl)phenyl](4-quinolyl)}[2- 530 C(4-piperidylmethyl)phenyl]amine I562-methyl-N-(4-{4-[(3-piperidylpropyl)amino](2- 431 Bquinolyl)}phenyl)propanamide I57phenyl-N-(4-{4-[(3-piperidylpropyl)amino](2- 465 Aquinolyl)}phenyl)carboxamide I583-[N-(4-{4-[(3-piperidylpropyl)amino]-2- 461 Bquinolyl}phenyl)carbamoyl]propanoic acid I59 N-(2-cyanoethyl)(4-{4-[(3-442 A piperidylpropyl)amino](2- quinolyl)}phenyl)carboxamide I60N-ethyl-N-methyl(4-{4-[(3- 430 B piperidylpropyl)amino](2-quinolyl)}phenyl)carboxamide I61 N-(methylethyl)(4-{4-[(3- 431 Bpiperidylpropyl)amino](2- quinolyl)}phenyl)carboxamide I62N-ethyl(4-{4-[(3-piperidylpropyl)amino](2- 417 Bquinolyl)}phenyl)carboxamide I63 (4-{4-[(3-piperidylpropyl)amino](2- 471B quinolyl)}phenyl)-N-(2,2,2- trifluoroethyl)carboxamide I64N-(oxolan-2-ylmethyl)(4-{4-[(3- 473 B piperidylpropyl)amino](2-quinolyl)}phenyl)carboxamide I65 ethyl2-[(4-{4-[(3-piperidylpropyl)amino]-2- 475 Aquinolyl}phenyl)carbonylamino]acetate I66N-[2-(dimethylamino)ethyl](4-{4-[(3- 460 A piperidylpropyl)amino](2-quinolyl)}phenyl)carboxamide I67 N-(3-hydroxypropyl)(4-{4-[(3- 447 Apiperidylpropyl)amino](2- quinolyl)}phenyl)carboxamide I682-[(4-{4-[(3-piperidylpropyl)amino]-2- 447 Bquinolyl}phenyl)carbonylamino]acetic acid I69 methyl2-[(4-{4-[(3-piperidylpropyl)amino]-2- 461 Bquinolyl}phenyl)carbonylamino]acetate I70N-cyclopropyl(4-{4-[(3-piperidylpropyl)amino](2- 430 Bquinolyl)}phenyl)carboxamide I71N,N-diethyl(4-{4-[(3-piperidylpropyl)amino](2- 445 Aquinolyl)}phenyl)carboxamide I72N,N-dimethyl(4-{4-[(3-piperidylpropyl)amino](2- 417 Bquinolyl)}phenyl)carboxamide I73N-methyl(4-{4-[(3-piperidylpropyl)amino](2- 403 Bquinolyl)}phenyl)carboxamide I74 4-{4-[(3-piperidylpropyl)amino]-2- 389A quinolyl}benzamide I75 (2-{[2,4-bis(trifluoromethyl)phenyl]amino}(4-497 C quinolyl))(3-piperidylpropyl)amine I76{2-[(3-chlorophenyl)amino](4-quinolyl)}(3- 395 C piperidylpropyl)amineI77 N-(4-{4-[(3-piperidylpropyl)amino](2- 471 Bquinolyl)}-2-(trifluoromethyl)phenyl)acetamide I78(2-benzo[b]thiophen-6-yl(4-quinolyl))(3- 402 A piperidylpropyl)amine I793-{4-[(3-piperidylpropyl)amino]-2- 418 B quinolyl]phenyl)methyl acetateI80 3-amino-5-{4-[(3-piperidylpropyl)amino](2- 474 B quinolyl)}phenylmorpholin-4-yl ketone I81 2-fluoro-4-{4-[(3-piperidylpropyl)amino](2-407 A quinolyl)}benzamide I822-chloro-4-{4-[(3-piperidylpropyl)amino](2- 423 A quinolyl)}benzamideI83 3-methyl-5-{4-[(3-piperidylpropyl)amino](2- 386 Bquinolyl)}pyridine-2-carbonitrile I84 4-{4-[(3-piperidylpropyl)amino](2-443 B quinolyl)}phenyl pyrrolidinyl ketone I85[2-(3,5-difluorophenyl)(4-quinolyl)](3- 382 B piperidylpropyl)amine I86(3-piperidylpropyl)[2-(2,4,5-trifluorophenyl)(4- 400 B quinolyl)]amineI87 (3-piperidylpropyl)(2-{6-[4- 507 B(trifluoromethyl)phenoxy](3-pyridyl)}(4- quinolyl))amine I88{2-[3-chloro-2-(phenylmethoxy)(4-pyridyl)](4- 488 Bquinolyl)}(3-piperidylpropyl)amine I89[2-(5-bromo-2-methoxy(4-pyridyl))(4-quinolyl)](3- 456 Bpiperidylpropyl)amine I90 [2-(2,6-difluoro(3-pyridyl))(4-quinolyl)](3-383 B piperidylpropyl)amine I91[2-(3-chloro-2-prop-2-enyloxy(4-pyridyl))(4- 467 Cquinolyl)](3-piperidylpropyl)amine I92[2-(5-methylthio(3-pyridyl))(4-quinolyl)](3- 393 B piperidylpropyl)amineI93 [2-(2-butoxy(3-pyridyl))(4-quinolyl)](3- 419 B piperidylpropyl)amineI94 [2-(3-fluoro(2-pyridyl))(4-quinolyl)](3- 365 B piperidylpropyl)amineI95 {2-[5-chloro-2-(cyclopropylmethoxy)(3- 452 Bpyridyl)](4-quinolyl)}(3-piperidylpropyl)amine I96[2-(2-ethoxy(3-pyridyl))(4-quinolyl)](3- 391 B piperidylpropyl)amine I97[2-(6-fluoro(2-pyridyl))(4-quinolyl)](3- 365 B piperidylpropyl)amine I98tert-butyl 2-{4-[(3-piperidylpropyl)amino]-2- 485 Cquinolyl}indolecarboxylate I99 [2-(2-chloro(3-pyridyl))(4-quinolyl)](3-381 B piperidylpropyl)amine I100 [2-(2,6-dichlorophenyl)(4-quinolyl)](3-415 C piperidylpropyl)amine I101 2-(3-bromo-4-chloro-2-fluorophenyl)(4-477 B quinolyl)](3-piperidylpropyl)amine I102[2-(2-chloro(4-pyridyl))(4-quinolyl)](3- 381 B piperidylpropyl)amineI103 [2-(2,4-dichlorophenyl)(4-quinolyl)](3- 415 B piperidylpropyl)amineI104 [2-(2-ethoxy(3-pyridyl))(4-quinolyl)](3- 391 Bpiperidylpropyl)amine I105 {2-[5-ethoxy-2-(trifluoromethyl)phenyl](4-458 B quinolyl)}(3-piperidylpropyl)amine I106dimethyl[(3-{4-[(3-piperidylpropyl)amino](2- 521 B quinolyl)}-4-(trifluoromethyl)phenyl)sulfonyl]amine I1072-(2,5-dimethylphenyl)(4-quinolyl)](3- 374 B piperidylpropyl)amine I108[2-(3,4-dimethoxyphenyl)(4-quinolyl)](3- 406 B piperidylpropyl)amineI109 [2-(1-methylindol-5-yl)(4-quinolyl)](3- 399 A piperidylpropyl)amineI110 (2-indol-5-yl(4-quinolyl))(3-piperidylpropyl)amine 385 B I111(2-benzimidazol-6-yl(4-quinolyl))(3- 386 B piperidylpropyl)amine I112[2-(3,5-dimethylisoxazol-4-yl)(4-quinolyl)](3- 365 Cpiperidylpropyl)amine I113 [2-(4-(2H-3,4,5,6-tetrahydropyran-2- 446 Byloxy)phenyl)(4-quinolyl)](3- piperidylpropyl)amine I114{2-[4-methylthio-2-(trifluoromethyl)phenyl](4- 460 Bquinolyl)}(3-piperidylpropyl)amine I115(3-piperidylpropyl)[2-(2,3,4-trifluorophenyl)(4- 400 B quinolyl)]amineI116 N-(2-{4-[(3-piperidylpropyl)amino]-2- 403 Cquinolyl}phenyl)acetamide I117 N-(4-{4-[(3-piperidylpropyl)amino]-2- 403B quinolyl}phenyl)acetamide I118 N-(3-{4-[(3-piperidylpropyl)amino]-2-403 B quinolyl}phenyl) acetamide I119{2-[4-chloro-2-(trifluoromethyl)phenyl](4- 448 Bquinolyl)}(3-piperidylpropyl)amine I120{2-[2-chloro-4-(trifluoromethyl)phenyl](4- 448 B quinolyl)}(3- I1214-(methylsulfonyl)-1-{4-[(3- 492 Bpiperidylpropyl)amino](2-quinolyl)}-2- (trifluoromethyl)benzene I122{2-[4-fluoro-2-(trifluoromethyl)phenyl](4- 432 Bquinolyl)}(3-piperidylpropyl)amine I1233-{4-[(3-piperidylpropyl)amino]-2- 389 B quinolyl}benzamide I124(2-indol-2-yl(4-quinolyl))(3-piperidylpropyl)amine 385 C I125(2-(2H,3H-benzo[3,4-e]1,4-dioxin-6-yl)(4- 404 Bquinolyl))(3-piperidylpropyl)amine I1262-(4-chloro-2-fluorophenyl)(4-quinolyl)](3- 398 A piperidylpropyl)amineI127 (3-piperidylpropyl)[2-(3,4,5-trifluorophenyl)(4- 399 Bquinolyl)]amine I128 3-{4-[(3-piperidylpropyl)amino]-2- 390 Bquinolyl}benzoic acid I129 dimethyl(3-{4-[(3-piperidylpropyl)amino](2-389 B quinolyl)}phenyl)amine I130[2-(2,6-difluorophenyl)(4-quinolyl)](3- 382 B piperidylpropyl)amine I131(3-piperidylpropyl){2-[2-(2,2,2- 444 Btrifluoroethoxy)phenyl](4-quinolyl)}amine I1324-(methylsulfonyl)-1-{4-[(3- 424 Bpiperidylpropyl)amino](2-quinolyl)}benzene I133[2-(5-chloro-2-methoxyphenyl)(4-quinolyl)](3- 410 Bpiperidylpropyl)amine I134 [2-(4-chloro-2-methylphenyl)(4-quinolyl)](3-394 B piperidylpropyl)amine I135{2-[4-(methoxymethyl)phenyl](4-quinolyl)}(3- 390 A piperidylpropyl)amineI136 (3-piperidylpropyl)(2-(3-thienyl)(4- 352 C quinolyl))amine I137ethyl 3-{4-[(3-piperidylpropyl)amino]-2- 418 B quinolyl}benzoate I138[2-(3,4-dichlorophenyl)(4-quinolyl)](3- 415 B piperidylpropyl)amine I139(3-piperidylpropyl)(2-(4-pyridyl)(4- 347 B quinolyl))amine I140(2-benzo[b]thiophen-2-yl(4-quinolyl))(3- 402 B piperidylpropyl)amineI141 [2-(2,4-dimethoxypyrimidin-5-yl)(4- 408 Bquinolyl)](3-piperidylpropyl)amine I142[2-(5-chloro(2-thienyl))(4-quinolyl)](3- 386 B piperidylpropyl)amineI143 (3-piperidylpropyl)(2-pyrimidin-5-yl(4- 348 B quinolyl))amine I144(3-piperidylpropyl)(2-(2-thienyl)(4- 352 B quinolyl))amine I145{2-[3-(1,1-dimethyl-1-silaethyl)phenyl](4- 418 Bquinolyl)}(3-piperidylpropyl)amine I146 1-(methylsulfonyl)-3-{4-[(3- 424B piperidylpropyl)amino](2-quinolyl)}benzene I147(3-piperidylpropyl)(2-(3-pyridyl)(4- 346 B quinolyl))amine I148{2-[4-(aminomethyl)phenyl](4- 375 A quinolyl)}(3-piperidylpropyl)amineI149 {2-[2,4-bis(trifluoromethyl)phenyl](4- 482 Aquinolyl)}(3-piperidylpropyl)amine I1502-{4-[(3-piperidylpropyl)amino]-2- 371 A quinolyl}benzenecarbonitrileI151 (2-methyl(4-quinolyl))(3-piperidylpropyl)amine 284 C I152{2-[5-nitro-2-(trifluoromethyl)phenyl](4- 459 Bquinolyl)}(3-piperidylpropyl)amine I153(3-piperidylpropyl){2-[2-(trifluoromethyl)(3- 415 Bpyridyl)](4-quinolyl)}amine I154[2-(2-methoxy(3-pyridyl))(4-quinolyl)](3- 377 B piperidylpropyl)amineI155 methyl 3-{4-[(3-piperidylpropyl)amino]-2- 403 B quinolyl}benzoateI156 [2-(6-methoxy(3-pyridyl))(4-quinolyl)](3- 377 Bpiperidylpropyl)amine I157 [2-(4-methylphenyl)(4-quinolyl)](3- 360 Bpiperidylpropyl)amine I158 [2-(2-methylthiophenyl)(4-quinolyl)](3- 392 Apiperidylpropyl)amine I159 [2-(2-methylphenyl)(4-quinolyl)](3- 360 Bpiperidylpropyl)amine I160 4-{4-[(3-piperidylpropyl)amino]-2- 390 Bquinolyl}benzoic acid I161 [2-(2,3-dimethylphenyl)(4-quinolyl)](3- 374 Bpiperidylpropyl)amine I162 [2-(3-fluorophenyl)(4-quinolyl)](3- 364 Bpiperidylpropyl)amine I163(2-phenyl(4-quinolyl))(3-piperidylpropyl)amine 346 B I164[2-(2-fluoro-6-methoxyphenyl)(4-quinolyl)](3- 394 Bpiperidylpropyl)amine I165 [2-(3-methoxyphenyl)(4-quinolyl)](3- 376 Bpiperidylpropyl)amine I166 (3-piperidylpropyl){2-[2- 430 A(trifluoromethoxy)phenyl](4-quinolyl)}amine I167(2-(2H-benzo[3,4-d]1,3-dioxolen-5-yl)(4- 390 Bquinolyl))(3-piperidylpropyl)amine I168{2-[2,4-bis(trifluoromethyl)phenyl](4- 462 Aquinolyl)}(3-piperidylpropyl)amine I1692-(4-methylthiophenyl)(4-quinolyl)](3- 392 B piperidylpropyl)amine I170[2-(3,5-dichlorophenyl)(4-quinolyl)](3- 415 B piperidylpropyl)amine I1714-{4-[(3-piperidylpropyl)amino]-2- 371 B quinolyl}benzenecarbonitrileI172 [2-(2,6-dimethoxyphenyl)(4-quinolyl)](3- 406 Cpiperidylpropyl)amine I173 [2-(2,5-dimethoxyphenyl)(4-quinolyl)](3- 406B piperidylpropyl)amine I174 [2-(2,4-dimethoxyphenyl)(4-quinolyl)](3-406 B piperidylpropyl)amine I175 (3-piperidylpropyl)(2-pyrrol-2-yl(4-335 B quinolyl))amine I176 [2-(2,4-dimethyl(1,3-thiazol-5-yl))(4- 381 Bquinolyl)](3-piperidylpropyl)amine I177(2-(3-furyl)(4-quinolyl))(3-piperidylpropyl)amine 336 B I178[2-(1-methylpyrazol-3-yl)(4-quinolyl)](3- 350 C piperidylpropyl)amineI179 (3-morpholin-4-ylpropyl)(2-phenyl(4- 348 C quinolyl))amine I180(2-morpholin-4-ylethyl)(2-phenyl(4- 348 B quinolyl))amine I181(2-phenyl(4-quinolyl))(2-pyrrolidinylethyl)amine 318 C I182(2-phenyl(4-quinolyl))(3-piperidylpropyl)amine 346 B I183dimethyl{2-[(2-phenyl(4- 292 C quinolyl))amino]ethyl}amine I184(2-morpholin-4-ylethyl)(2-phenylquinazolin-4- 335 C yl)amine I185(2-phenylquinazolin-4-yl)(3-piperidylpropyl)amine 347 C I1862-phenyl-4-(3-piperidylpropoxy)quinoline 347 C I187[2-(4-chlorophenyl)(4-quinolyl)](3- 380 B piperidylpropyl)amine I188[2-(4-fluorophenyl)(4-quinolyl)](3- 364 B piperidylpropyl)amine I189(4-{4-[(3-piperidylpropyl)amino](2- 494 A quinolyl)}phenyl)-N-(2-(4-pyridyl)ethyl)carboxamide I190 N-[3-(diethylamino)propyl](4-{4-[(3- 502A piperidylpropyl)amino](2- quinolyl)}phenyl)carboxamide I191N-(2-piperidylethyl)(4-{4-[(3- 500 A piperidylpropyl)amino](2-quinolyl)}phenyl)carboxamide I192 N-(3-morpholin-4-ylpropyl)(4-{4-[(3-516 A piperidylpropyl)amino](2- quinolyl)}phenyl)carboxamide I193piperazinyl 4-{4-[(3-piperidylpropyl)amino](2- 458 A quinolyl)}phenylketone I194 piperidyl 4-{4-[(3-piperidylpropyl)amino](2- 457 Bquinolyl)}phenyl ketone I195 N-(3-aminopropyl)(4-{4-[(3- 446 Apiperidylpropyl)amino](2- quinolyl)}phenyl)carboxamide I196N-(4-piperidyl)(4-{4-[(3-piperidylpropyl)amino](2- 472 Aquinolyl)}phenyl)carboxamide I197 N-(4-piperidylmethyl)(4-{4-[(3- 486 Apiperidylpropyl)amino](2- quinolyl)}phenyl)carboxamide I198N-(3-piperidylpropyl)(4-{4-[(3- 514 A piperidylpropyl)amino](2-quinolyl)}phenyl)carboxamide I199[2-(4-methoxyphenyl)(4-quinolyl)](2-(2- 356 B pyridyl)ethyl)amine I200[2-(4-methoxyphenyl)(4-quinolyl)](3-(4- 370 B pyridyl)propyl)amine I201[2-(4-methoxyphenyl)(4-quinolyl)](2-(4- 356 B pyridyl)ethyl)amine I2022-(3-chlorophenyl)(4-quinolyl)](3-(3- 374 B pyridyl)propyl)amine I2032-(4-methoxyphenyl)(4-quinolyl)](3-(3- 370 B pyridyl)propyl)amine I204[2-(4-chloro-2-fluorophenyl)(4-quinolyl)](3-(3- 392 Bpyridyl)propyl)amine I205 [2-(4-(1H-1,2,3,4-tetraazol-5-yl)phenyl)(4-414 B quinolyl)](3-piperidylpropyl)amine I206{4-[(4-ethylpiperazinyl)methyl]phenyl([2-(4- 457 Bmethoxyphenyl)(4-5,6,7,8- tetrahydroquinolyl)]amine I207[2-(4-methoxyphenyl)(4-5,6,7,8- 430 B tetrahydroquinolyl)][4-(piperidylmethyl)phenyl]amine I208 [2-(4-methoxyphenyl)(4-5,6,7,8- 380 Btetrahydroquinolyl)](3-piperidylpropyl)amine I209[2-(4-methoxyphenyl)(4-5,6,7,8- 414 B tetrahydroquinolyl)][3-(pyrrolidinylmethyl)phenyl]amine I210[2-(4-methoxyphenyl)(4-quinolyl)]{[4- 438 B(piperidylmethyl)phenyl]methyl}amine I211[2-(4-methoxyphenyl)(4-quinolyl)]{[4-(morpholin- 440 B4-ylmethyl)phenyl]methyl}amine I212 4-[4-({[4-(morpholin-4- 453 Cylmethyl)phenyl]methyl}amino)-2- quinolyl]benzamide I2134-[4-({[4-(piperidylmethyl)phenyl]methyl}amino)- 451 C2-quinolyl]benzamide I214 4-{4-[({4-[(4- 480 Cethylpiperazinyl)methyl]phenyl}methyl)amino]-2- quinolyl}benzamide I2154-[4-({4-[(4- 466 C ethylpiperazinyl)methyl]phenyl}amino)-2-quinolyl]benzamide I216 4-(4-{[4-(2-piperazinylethyl)phenyl]amino}-2-452 C quinolyl)benzamide I2174-[4-({4-[2-(dimethylamino)ethyl]phenyl}amino)- 411 C2-quinolyl]benzamide I218 4-(4-{[3-(diethylamino)propyl]amino}-2- 377 Cquinolyl)benzamide I219 4-{4-[(3-azaperhydroepinylpropyl)amino]-2- 403 Cquinolyl}benzamide I220 4-(4-{[4-(4-piperidylmethyl)phenyl]amino}-2- 437C quinolyl)benzamide I221 6-{4-[(3-piperidylpropyl)amino]-2- 401 Bquinolyl}indolin-2-one I222 4-(4-{4-[(4-aminophenyl)methyl]piperidyl}-2-437 C quinolyl)benzamide I223 {2-[3-fluoro-2-(trifluoromethyl)phenyl](4-432 B quinolyl)}(3-piperidylpropyl)amine I224(2-benzothiazol-5-yl(4-quinolyl))(3- 403 B piperidylpropyl)amine I225{2-[4-(4-fluorophenyl)phenyl](4-quinolyl)}(3- 440 Bpiperidylpropyl)amine I226 N-(2-methylpropyl)(4-{4-[(3- 445 Bpiperidylpropyl)amino](2- quinolyl)}phenyl)carboxamide I227N-(2-hydroxyethyl)(4-{4-[(3- 433 B piperidylpropyl)amino](2-quinolyl)}phenyl)carboxamide I228(2-fluoro-4-{4-[(3-piperidylpropyl)amino](2- 421 Bquinolyl)}phenyl)-N-methylcarboxamide I229 N-ethyl(2-fluoro-4-{4-[(3-435 B piperidylpropyl)amino] (2- quinolyl)}phenyl)carboxamide I230N-cyclohexyl(4-{4-[(3-piperidylpropyl)amino](2- 471 Bquinolyl)}phenyl)carboxamide I231 N-(4-{4-[(3-piperidylpropyl)amino](2-471 B quinolyl)}-2-(trifluoromethyl)phenyl)acetamide I232N-(2-fluoro-4-{4-[(3-piperidylpropyl)amino](2- 421 Bquinolyl)}phenyl)acetamide I233 4-[(2-{4-[(3-piperidylpropyl)amino]-2-495 C quinolyl}phenyl)sulfonyl]morpholine I234 morpholin-4-yl4-{4-[(3-piperidylpropyl)amino](2- 459 A quinolyl)}phenyl ketone I2354-[(4-{4-[(3-piperidylpropyl)amino]-2- 511 Aquinolyl}phenyl)sulfonyl]-1,4-thiazaperhydroine I2364-[(4-{4-[(3-piperidylpropyl)amino]-2- 495 Aquinolyl}phenyl)sulfonyl]morpholine I237 N-{3-[4-({3-[(1-ethyl-4- 479 Bpiperidyl)methyl]phenyl}amino)-2- quinolyl]phenyl}acetamide I238[2-(3-chloro-2-fluorophenyl)(4-quinolyl)](3- 398 B piperidylpropyl)amineI239 [2-(5-bromo-3-chloro-2-fluorophenyl)(4- 477 Bquinolyl)](3-piperidylpropyl)amine I240diethyl[(2-{4-[(3-piperidylpropyl)amino](2- 481 Cquinolyl)}phenyl)sulfonyl]amine I241(2-(2-4,5-dihydrofuryl)(4-quinolyl))(3- 338 C piperidylpropyl)amine I242diethyl[(4-methyl-3-{4-[(3- 495 C piperidylpropyl)amino](2-quinolyl)}phenyl)sulfonyl]amine I243 [2-(4-phenylphenyl)(4-quinolyl)](3-422 B piperidylpropyl)amine I244diethyl[(3-{4-[(3-piperidylpropyl)amino](2- 481 Cquinolyl)}phenyl)sulfonyl]amine I245 {2-[3-(phenylmethylthio)phenyl](4-468 C quinolyl)}(3-piperidylpropyl)amine I246diethyl[(4-{4-[(3-piperidylpropyl)amino](2- 481 Bquinolyl)}phenyl)sulfonyl]amine I247(2-benzo[b]thiophen-5-yl(4-quinolyl))(3- 402 A piperidylpropyl)amineI248 2-(2-methylbenzothiazol-6-yl)(4-quinolyl)](3- 417 Bpiperidylpropyl)amine I249N-cyclopentyl(4-{4-[(3-piperidylpropyl)amino](2- 457 Aquinolyl)}phenyl)carboxamide I250 5-(acetylamino)-3-{4-[(3- 447 Bpiperidylpropyl)amino](2-quinolyl)}benzoic acid I251(2-chloro-4-{4-[(3-piperidylpropyl)amino](2- 437 Aquinolyl)}phenyl)-N-methylcarboxamide I2523-fluoro-4-{4-[(3-piperidylpropyl)amino](2- 407 A quinolyl)}benzamideI253 N-benzyl(4-{4-[(3-piperidylpropyl)amino](2- 479 Aquinolyl)}phenyl)carboxamide I254 N-[2-(diethylamino)ethyl](4-{4-[(3-488 A piperidylpropyl)amino](2- quinolyl)}phenyl)carboxamide I255N-[(4-{4-[(3-piperidylpropyl)amino]-2- 417 Aquinolyl}phenyl)methyl]acetamide I256(2-acenaphthen-4-yl(4-quinolyl))(3- 422 A piperidylpropyl)amine I257(2-benzo[b]thiophen-6-yl(4-quinolyl))(3- 402 A piperidylpropyl)amineI258 (3-{4-[(3-piperidylpropyl)amino]-2- 418 B quinolyl}phenyl)methylacetate I259 3-amino-5-{4-[(3-piperidylpropyl)amino](2- 474 Bquinolyl)}phenyl morpholin-4-yl ketone I260 1-(phenylsulfonyl)-5-{4-[(3-525 B piperidylpropyl)amino](2-quinolyl)}indole I2612-fluoro-4-{4-[(3-piperidylpropyl)amino](2- 407 A quinolyl)}benzamideI262 2-methyl-N-(4-{4-[(3-piperidylpropyl)amino](2- 431 Bquinolyl)}phenyl)propanamide I263phenyl-N-(4-{4-[(3-piperidylpropyl)amino](2- 465 Aquinolyl)}phenyl)carboxamide I2642-chloro-4-{4-[(3-piperidylpropyl)amino](2- 423 A quinolyl)}benzamideI265 N-(2-cyanoethyl)(4-{4-[(3- 442 A piperidylpropyl)amino](2-quinolyl)}phenyl)carboxamide I266 N-ethyl-N-methyl(4-{4-[(3- 431 Bpiperidylpropyl)amino](2- quinolyl)}phenyl)carboxamide I267N-(methylethyl)(4-{4-[(3- 431 B piperidylpropyl)amino](2-quinolyl)}phenyl)carboxamide I268N-ethyl(4-{4-[(3-piperidylpropyl)amino](2- 417 Bquinolyl)}phenyl)carboxamide I269 (4-{4-[(3-piperidylpropyl)amino](2-471 B quinolyl)}phenyl)-N-(2,2,2- trifluoroethyl)carboxamide I270N-(oxolan-2-ylmethyl)(4-{4-[(3- 473 B piperidylpropyl)amino](2-quinolyl)}phenyl)carboxamide I271N-cyclopropyl(4-{4-[(3-piperidylpropyl)amino](2- 429 Bquinolyl)}phenyl)carboxamide I272 4-{4-[(3-piperidylpropyl)amino](2- 443B quinolyl)}phenyl pyrrolidinyl ketone I273[2-(3,5-difluorophenyl)(4-quinolyl)](3- 382 B piperidylpropyl)amine

Example 4: SAR Analysis

Two initial compounds were selected (Scheme 4).

The most potent scaffold discovered was the quinoline compound(IC₅₀=3.49 μM) The second scaffold identified was the quinazolinonecompound (IC₅₀=7.12 μM).

The initial SAR strategy focused on the quinazolinone series. The SARstrategy for the quinazolinone series is outlined in FIG. 15.

First, at the R₁ position the inventors investigated the effects ofchanging the chain length, looking at the effects of branching on thechain, adding substituents on the chain, both aromatic andheteroaromatic, and the inventors investigated the substitution ofcycloamino groups on the alkyl chain. For the R₂ group the inventorsinvestigated the effects electron donating and electron withdrawinggroups on the activity of the parent series. For all SAR tables shownbelow: P=purchased compounds, CP=cherry pick of 10 μM DMSO solutionsfrom the NIH MLSMR library and S=synthesized compounds.

Table 1 summarizes studies on the quinazoline series of compounds.

TABLE 1 SAR explorations of the quinazoline core (Entries 1-7)

LMPTP (OMFP) Entry P/S* R₁ R₂ R₃ (IC₅₀) (μM) n SEM  1 Screen hit CP P

3-CH₃ H   7.12 13.5 3 4 0.72 0.71  2 CP P

2-F H 22.0 13.0 3 4 2.31 3.31  3 CP P

4-CH₃ H 16.0 18.8 3 4 1.02 0.93  4 CP

H H 17   3 4.40  5 CP P

H H   8.37 19.0 3 4 0.82 2.66  6 CP P

4-CH₃ H   8.04 12.9 3 4 0.46 1.74  7 CP

H H 17.0 4 3.85  8 CP P

H H 13.9 17.8 3 4 2.01 1.09  9 CP

H H 23.1 3 2.22 10 CP P

H H 11.8 20.9 3 4 0.28 2.21 11 CP P

H H   7.51 24.2 3 4 1.69 1.53 12 CP

4-O(i-Pr) H 18.1 3 1.20 13 CP

H H 9.94 3 2.25 14 CP

2-F H 5.48 3 0.21 15 CP

H H 7.48 3 1.49 16 P

4-NO₂ H 10.9 3 2.84 17 CP

4-NO₂ H >80     4 — 18 P

H H 18.1 4 1.29 19 CP

H H 12.0 3 0.49 20 CP P

H H 10.0 21.1 3 4 0.65 2.02 21 CP

H H 12.3 3 2.04 22 S

H H 72.2 2 5.38 23 S

H H >80     3 — 24 S

H H >80     3 — 25 S

H H >80     3 — 26 S

H H >80     3 — 27 S

H H 53.1 4 1.27 28 S

H H >80     3 — 29 S

H H 14.5 4 0.98 30 S

H H 23.2 4 1.72 31 S

H H 15.0 4 1.04 32 S

H H 48.1 4 3.25 33 S

H H >80     4 — 34 S

H H 19.1 4 1.49 35 S

H H 64.3 4 6.90 36 S

H H >80     4 — 37 S

H H 22.5 4 1.76 38 S

H H 25.4 4 2.29 39 S

H H 21.9 4 2.12 40 S

H H 58.1 3 7.04 P = compounds purchased from commercial sources CP =“cherry pick” of 10 mM DMSO from NIH MLSMR S = compouond synthesized denovo by SBCCG

The initial hit compound in Table 1, (Entry 1), was obtained anddemonstrated similar potency to the solution screening sample (LMPTP(OMFP) IC₅₀=13.5 μM). The inventors found 20 additional analogs in thescreening collection and synthesized an additional 18 analogs for thequinazolinone series. From these analogs, the inventors first testedfour analogs where the R₁ group was fixed as a3-morpholinopropan-1-amine and different R₂ substituents on the phenylring were examined. In general the substitution at the C-2 position ofthe phenyl is favored and an electron donating group at this position isalso preferred (Entries 1-4). A similar observation was noted when theR₁ group was fixed and the C-2 position had a fluorine atom versus ahydrogen atom, the 2-F analogs were more potent. (Entry 9 and 14 andEntry 15 and 20). The inventors examined shorting the chain length at R₁coupled with having an aromatic/heteroaromatic group on the chain; forthese compounds the inventors observed little change in potency over thelead structure CID1566769. (Entries 5-7, 9, 13-14, 16-17). Oneinteresting observation was when the cycloalkyl or cycloheteroalkylgroup was attached directly to the ring with no carbon spacer thecompounds were inactive. (Entries 22-26, 28, 33). When the R₁ group wasan amine containing 2-4 carbon atoms, branched or straight chain, allthe compounds had similar potencies (Entries 27, 29-31). Finally, whencompounds with similar R₁ groups differing by only one carbon atom inthe chain were compared the potencies were similar. (Entries 35 and 39,Entries 37 and 38).

Table 2 summarizes studies on the quinolone series of compounds.

TABLE 2 SAR explorations of the quinazoline core (Entries 1-7)

LMPTP (OMFP) Entry P/S* R₁ R₂ R₃ (IC₅₀) (μM) n SEM 41 Screen hit CP P S

H H  3.49  2.86  3.70 3 4 4 0.62 0.10 0.36 42 CP P

H H  9.25 11.1 3 4 1.32 0.70 43 S

H H  7.68 4 0.71 44 S

H H  2.13 4 0.13 45 S

H H  5.46 4 0.58 46 S

H H  1.56 4 0.08 47 S

H H  5.72 4 0.53 48 S

4-Cl H  1.54 4 0.06 49 S

4-F H  1.40 4 0.09 50 (Compound D1) (MLS- 0472870) S

4-OCH₃ H  1.68 4 0.15 51 S

CH₃ H  1.34 4 0.08 52 S

2-Cl H 11.6 4 0.41 53 S

3-Cl H  1.12 4 0.20 54 S

3-CF₃ H  2.66 4 0.14 55 S

2-OCH₃ H  2.87 4 0.11 56 S

3-F H  1.84 4 0.10 57 S

3-OCH₃ H  2.21 4 0.15 58 S

H 6-F 22.0 4 7.35 59 S

H 6-Br >80     4 — 60 S

H 6-CH₃ >80     4 — 61 S

H 6,7-di- OCH₃ >80     4 — 62 S

H H 10.0 21.1 3 4 0.65 2.02 63 S

H H 11.5 4 0.91 64 S

H H 66.9 3 5.77 P = compounds purchased from commercial sources CP =“cherry pick” of 10 mM DMSO from NIH MLSMR S = compound synthesized denovo by SBCCG

A similar SAR strategy was applied to the quinolone series (FIG. 16).

For the R₁ group the inventors focused on either a 2 or 3 carbon spacerbetween the ring coupled nitrogen atom and the cycloalkyl orheterocycloalkyl tail groups. A limited number of R₂ groups wereinvestigated and a small set of R₃ analogs were synthesized.

The screening hit CID2728458 (Entry 41) was independently purchased andsynthesized and the activity of the purchased and synthesized compoundwas similar LMPTP (OMFP) IC₅₀=2.86 μM and LMPTP (OMFP) IC₅₀=3.70 μMrespectively. Screening of Entry 42 showed that the potency was lessthan the screening hit.

Overall, the inventors synthesized 21 compounds in the quinoline series,to ultimately select Entry 50 (CID73050863) for SAR explorations.

For the first set of SAR analogs, the inventors choose to fix R₂ and R₃as hydrogen atoms and vary the R₁ position. The most active member ofthis set of analogs (Entries 41-47) was the3-(piperidin-1-yl)propan-1-amine analog, Entry 46. (LMPTP (OMFP)IC₅₀=1.56 μM). Next we fixed the R₁ group as the3-(piperidin-1-yl)propan-1-amine moiety, the R₃ group as hydrogen atomand varied the R₂ substitution. Substitution around the phenylsubstituent R₂ indicated little preference for electron withdrawingmoieties over analogs containing electron donating groups, therespective LMPTP (OMFP) IC₅₀ values ranged from 1.12-2.86 μM range.(Table 2; entries 48-51, 53-57). In addition, no strong preferenceregarding position (ortho, meta, para) was determined with regards topotency, the notable exception being the 2-Cl analog Entry 52, LMPTP(OMFP) IC=11.2 μM. The third set of analogs fixed the R₁ group as the3-(piperidin-1-yl)propan-1-amine moiety, the R₂ group as hydrogen atomand varied the R₃ substitution. The compounds synthesized hadsubstituents at the C-6 or C-6, C-7 positions of the quinoline ring andall the compounds lost significant potency with these modifications.(Table 2; entries 58-61). Finally the inventors replaced the nitrogenatom attached directly to the quinoline ring of Entry 50 (Compound D1 ofExample 1) with either an oxygen or sulfur atom and the compounds wereinactive. (Entries 63-64).

Example 5: Cell Based Activity and Efficacy

The probe Compound D1 was also profiled in an insulin-based mouse 3T3-L1adipogenesis assay. In this assay, 3T3-L1 pre-adipocytes are grown to2-days post-confluence in DMEM with 10% bovine calf serum, and theninduced to differentiate to adipocytes following stimulation for 2 dayswith an induction cocktail containing 1 jag/ml insulin, 1 μMdexamethasone, and 0.5 mM 3-isobutyl-1-methylxanthine in DMEM containing10% fetal bovine serum (FBS).⁴⁴ 2 days later, the media is replaced withDMEM with 10% FBS and 1 μg/ml insulin, and after 2 additional days, themedia is replaced with DMEM with 10% FBS for 2 additional days, at whichpoint adipogenesis is measured using the AdipoRed Adipogenesis AssayReagent from Lonza, according to the manufacturer's instructions. Inbrief, the assay reagent is added to the wells containing cells, whereit partitions into the fat droplets of differentiated adipocytes, andemits fluorescence at 572 nm that can be detected with a plate-reader.To test the effect of probe Compound D1, cells were plated into 48-wellplates and allowed to grow to confluence. Cells were then treated with10 μM Compound D1 or 0.025% DMSO, and after 2 days induced todifferentiate in the presence of 10 μM Compound D1 or 0.025% DMSO. Freshcompound or DMSO was added during each media replacement. As shown inthe FIG. 7, it was found that treatment with 10 μM Compound D1completely abolished 3T3-L1 adipogenesis.

ADME/T Profiling Assays

In the course of this investigation many compounds with similarpotencies in the LMPTP (OMFP) assay were found. In order to determinewhich compound would be the best candidate for in vivo studies, anabbreviated ADME panel was ran on these compounds, a tabulation of themost interesting data on this set of compounds is illustrated in Table 3below. From the hepatic microsome stability data the candidate selectedfor in vivo studies was Compound D1.

TABLE 3 Summary of in vitro ADME Properties of selected LMPTP inhibitorsAqueous Hepatic Microsome Com- Solubility Pion's Plasma StabilityStability pound buffer (ug/mL) % Remaining @ % Remaining @ ID (Entry) pH5.0/6.2/7.4 3 hrs Human/Mouse 1 hr Human/Mouse 41 111.8/95.7/54.570.08/62.25 26.54/0.38 48 >113/>113/>113  100/59.47  23.10/15.38 50(Com- >112/>112/>112 89.03/68.97  61.56/48.75 pound D1)51 >178/>178/>178 92.17/46.01 32.21/9.70 53 >99/>99/>99 82.81/50.1677.96/9.71 54 122.8/118.4/111.2 77.58/70.55 82.50/8.59 55 >103/>103/>10383.67/63.60 52.95/2.62

Compound D1 achieved very good concentrations 18-20×IC₅₀ in aqueousbuffer between a pH range of 5.0-7.4. The solubility was comparable inPBS. See FIG. 12.

Plasma stability is a measure of the stability of small molecules andpeptides in plasma and is an important parameter, which can stronglyinfluence the in vivo efficacy of a test compound. Drug candidates areexposed to enzymatic processes (proteinases, esterases) in plasma, andthey can undergo intramolecular rearrangement or bind irreversibly(covalently) to proteins. Compound D1 showed good stability in bothhuman plasma and mouse plasma.

The microsomal stability assay is commonly used to rank compoundsaccording to their metabolic stability. This assay addresses thepharmacologic question of how long the parent compound will remaincirculating in plasma within the body. Compound D1 showed moderatestability in human and mouse liver microsomes after 1 hour.

Example 6: Rodent Pharmacokinetics

The inventors also examined ML400 (also described herein as MLS-0472870or Compound D1) for its rodent pharmacokinetics. The probe Compound D1was profiled in Male C57BL/6 Mice, with n=3 for each group studied (IV,IP and PO arms). The formulation used was 1.00 mg/mL inDMSO:Tween80:Water=5:5:90, which gave a clear solution. Low clearanceand large volume of distribution were observed from IV arm andbioavailability was very good for PO and IP studies. Enterohepaticcirculation was also observed for this compound. This compound hasacceptable parameters for future in vivo studies (see Table 4 and FIG.13).

TABLE 4 Summary of in vivo Properties of LMPTP inhibitor probe CompoundD1 Parameter Route of Administration Study Group IV PO IP AdministeredDose 4.89 29.6 9.69 (mg/kg) t_(max) (h) 3.33 0.33 C_(max) (ng/mL) 3,210365 t_(1/2) (h) 39.6 29.2 32.5 Cl (mL/min/kg) 25.8 Vdss (L/kg) 83.1AUC_(0-inf) (ng · h/mL) 3,296 6,377 4,522 Bioavailability (% F) 40.5 78

Example 7: Dose Response

LYP-1 and VHR-1 dose response assays to assess selectivity of CompoundD1 against these non-homologous phosphatases. This data are summarizedin FIG. 14.

Example 8 Gene Trapping of the Acp1 Locus Abolishes Lmptp Expression

FIG. 1A shows localization of the gene-trap in the Acp1 gene. Exon 3 andexon 4 are alternatively spliced to generate Lmptp-A and -B isoforms.FIG. 1B shows PCR-based mouse genotyping using a forward primer located5′ to the gene-trap, a forward primer within the gene-trap, and areverse primer located 3′ to the gene-trap. FIG. 1C shows RT-PCR withLmptp primers on RNA extracted from the liver of a KO mouse andheterozygous and wild-type (WT) littermates. FIG. 1D shows anti-LmptpWestern blot and control anti-tubulin blot of liver lysates of a KOmouse and heterozygous and WT littermates.

LMPTP KO Decreases Diabetes of Obese Mice

FIGS. 2A-2D show that genetic deletion of LMPTP attenuates diabetes ofobese mice. (A-D) Male wild-type (WT) and LMPTP KO mice on C57BL/6background were placed on high-fat diet (HFD; 60% kcal from fat) for 3months starting at 2 months of age. (A) Weight curves over the course ofthe HFD. (B) Intraperitoneal glucose tolerance test (IPGTT) wasperformed on mice at 2 months of age, prior to the start of the HFD.Mice were fasted overnight and injected with 1 g glucose/kg body weight,and blood glucose levels were measured at the indicated times. (C) IPGTTwas performed on mice after 3 months HFD. (D) Fasting serum insulinlevels were assessed by ELISA. (A-D) Mean±SEM is shown. *p<0.05; NS,non-significant: Two-Way ANOVA (A, B, C) or Wilcoxon matched-pairssigned rank test (D).

LMPTP Knockdown Impairs Adipogenesis

FIG. 3 shows that knockdown of Lmptp with antisense oligonucleotides(ASO) impairs adipogenesis of 3T3-L1 cells. 3T3-L1 cells were subjectedto insulin-stimulated adipogenesis (as described in Example 5,describing cell based activity and efficacy) in the presence of 10 μMnon-targeting (Ctl) or Lmptp ASO. Intracellular lipid accumulation wasmeasured using the Lonza AdipoRed Assay Reagent. Mean±SD relativefluorescence units (RFU) are shown. *, p<0.05.

LMPTP-A Isoform Dephosphorylates Insulin Receptor (IR)

The LMPTP-A isoform dephosphorylates the IR. The IR wasimmunoprecipitated from liver homogenates of mice subjected to 5 minstimulation with insulin (5 U intracardiac). Panels show WB ofimmunoprecipitates following incubation with 5 nM recombinant LMPTP-A,LMPTP-B or PTP1B or no enzyme for 30 min at 37° C. in 50 mM Bis-Tris, pH6.0, 1 mM DTT. See FIG. 4.

Compound D1 Inhibits LMPTP with an Uncompetitive Mechanism of Action

Compound D1 (ML400) inhibits LMPTP with an uncompetitive mechanism ofaction, lowering both Vmax and KM. Activity of 20 nM LMPTP on OMFPsubstrate in the presence of increasing concentrations of ML400.Reactions were conducted at 37° C. in 50 mM Bis-Tris, pH 6.0 with 1 mMDTT and 0.01% Triton X-100. Mean±SD is shown. Lines show fitting of datato the Michaelis-Menten equation. Note decrease in both Vmax and KM withincreasing inhibitor concentration. See FIG. 5.

LMPTP Inhibitor Increases Phosphorylation of the Insulin Receptor inHepG2 Cells

Compound 41 of Table 2 shows efficacy in cellular assays. WB of IRimmunoprecipitation from human HepG2 hepatocytes incubated overnight inserum-starve culture media (containing 0.1% fetal bovine serum) in thepresence of 10 microM of Compound 41 of Table 2 or DMSO. Cells werestimulated with 1.76 microM insulin for 5 min prior to lysis. See FIG.6.

Compound D1 Treatment Improves Glucose Tolerance of Obese Mice

Male C57BL/6 mice were maintained on HFD containing 60 kcal % fat for 3months, followed by daily IP administration of 30 mg/kg Compound D1 orvehicle. After 4 weeks, IPGTT were performed using 2 g glucose/kg bodyweight. Mean±SEM is shown. *, p<0.05, Two-way ANOVA. See FIG. 8.

Compound D1 Treatment does not Affect Kidney Function

Serum creatinine levels from mice treated with Compound D1 (ML400) orvehicle (mice shown in FIG. 9) were assessed using the QuantiChromCreatinine Assay Kit from BioAssay Systems.

Compound D1 Treatment does not Affect Liver Function

Serum alanine transaminase or aspartate transaminase levels from micetreated with Compound D1 (ML400) or vehicle (mice shown in FIG. 10) wereassessed using EnzyChrom Assay Kits from BioAssay Systems.

The LMPTP Inhibitor Binds to LMPTP by Isothermal Calorimetry

ML400 analog G53 (Table A) binds to LMPTP. ITC was performed usingrecombinant human LMPTP-A and a derivative of Compound D1, G53. Kd=0.9microM.

Example 9

Additional information is provided in Tables 5, 6, 7, and 8(ML400=Compound D1).

TABLE 5 Table 5. Potency and selectivity characteristics for probeML-400 Secondary Assay(s) Names IC₅₀ (nM) Anti-target IC₅₀ (nM) Fold-IC₅₀(nm) CID/ML# Target Name [SID, AID] Name(s) [SID, AID] selective[SID, AID] CID LMPTP 1680 ± 150 LYP-1 >80 (n = 2) >60-fold LMPTP73050863 (low molecular (n = 4) (Lymphoid SID173019983 Orthogonal ML400weight protein SID173019983 phosphatase, AID743309 assay tyrosineAID686962 PTPN22) phosphatase) AID742207 VHR-1 >80 (n = 2) >60-fold 3520± 330 (Vaccine H1- SID173019983 (n = 2) related AID743310 SID173019983phosphatase) AID743308

TABLE 6 Table 6. Summary of Assays and AIDs Probe Assay Assay AssayDetect, PubChemBioAssay Name AIDs Type Type Format and well formatCenter Summary assay for small molecule 651562 Inhibitor Summary Bio-Fluoresc & SBCCG inhibitors of Low Molecular Weight chemical 1536 wellProtein Tyrosine Phosphatase, LMPTP uHTS identification of smallmolecule 651560 Inhibitor Primary Bio- Fluoresc & SBCCG inhibitors ofLow Molecular Weight chemical 1536 well Protein Tyrosine Phosphatase,LMPTP, via a fluorescence intensity assay Dose response confirmation forsmall 651700 Inhibitor Confirmatory Bio- Fluoresc & SBCCG moleculeinhibitors of Low Molecular (DMSO Dose chemical 1536 well Weight ProteinTyrosine Phosphatase, Response) LMPTP, via a fluorescence intensityassay Dose response confirmation for small 652005 Inhibitor OrthogonalBio- Fluoresc & SBCCG molecule inhibitors of Low Molecular (DMSO Dosechemical 1536 well Weight Protein Tyrosine Phosphatase, Response) LMPTP,in an orthogonal absorbance- based assay Dose response confirmation forsmall 652006 Inhibitor Selectivity Bio- Fluoresc & SBCCG moleculeinhibitors of Low Molecular (DMSO Dose chemical 1536 well Weight ProteinTyrosine Phosphatase, Response) LMPTP, in a fluorescence-based, LymphoidPhosphatase (PTPN22, LYP-1) selectivity assay Dose response confirmationof uHTS 686961 Inhibitor Selectivity Bio- Fluoresc & SBCCG smallmolecule inhibitors of Low (DMSO Dose chemical 1536 well MolecularWeight Protein Tyrosine Response) Phosphatase, LMPTP, in afluorescence-based, VHR-1 (dual specificity phosphatase 3) selectivityassay SAR confirmation of small molecule 686962 Inhibitor SAR (Dry Bio-Fluoresc & SBCCG inhibitors of Low Molecular Weight Powder) chemical1536 well Protein Tyrosine Phosphatase, LMPTP, via fluorescenceintensity assay SAR confirmation of small molecule 686963 Inhibitor SAR(Dry Bio- Fluorescence & SBCCG inhibitors of Low Molecular WeightPowder) chemical 1536 well Protein Tyrosine Phosphatase, LMPTP, in anorthogonal absorbance-based assay SAR confirmation of small molecule743307 Inhibitor SAR (Dry Bio- Fluoresc & SBCCG inhibitors of LowMolecular Weight Powder) chemical 1536 well Protein TyrosinePhosphatase, LMPTP, in a fluorescence intensity assay, set 2 SARconfirmation of small molecule 743308 Inhibitor SAR (Dry Bio- Fluoresc &SBCCG inhibitors of Low Molecular Weight Powder) chemical 1536 wellProtein Tyrosine Phosphatase, LMPTP, in an orthogonal absorbance-basedassay, set 2 SAR confirmation of small molecule 743309 Inhibitor SAR(Dry Bio- Fluoresc & SBCCG inhibitors of Low Molecular Weight Powder)chemical 1536 well Protein Tyrosine Phosphatase, LMPTP, in afluorescence-based, Lymphoid Phosphatase (PTPN22, LYP-1) selectivityassay SAR confirmation of small molecule 743310 Inhibitor SAR (Dry Bio-Fluoresc & SBCCG inhibitors of Low Molecular Weight Powder) chemical1536 well Protein Tyrosine Phosphatase, LMPTP, in a fluorescence-based,VHR-1 (dual specificity phosphatase 3) selectivity assay

TABLE 7 Table 7. Calculated Properties for ML-400 ML-400 CalculatedProperty CID73050863 Molecular Weight 421.53194 [g/mol] MolecularFormula C₂₅H₃₁N₃O₃ H-Bond Donor 2 H-Bond Acceptor 6 Rotatable Bond Count7 Exact Mass 421.236542 MonoIsotopic Mass 421.236542 Topological PolarSurface Area 74.7 Heavy Atom Count 31 Formal Charge 0 Complexity 455Isotope Atom Count 0 Defined Atom StereoCenter Count 0 Undefined AtomStereoCenter Count 0 Defined Bond StereoCenter Count 0 Undefined BondStereoCenter Count 0 Covalently-Bonded Unit Count 2

TABLE 8 Table 4. Probe and Analog Submissions to MLSMR (Evotec) forSmall Molecule Inhibitors of LMPTP Probe ML400 - CID73050863 Date Probe/MLS_ID MLS_ID Amt ordered/ Analog (SBCCG) (MLSMR) CID SID Source (mg)Submitted Probe ML400 0472870 MLS005939925 73050863 173019983 Synthesis27 Apr. 15, 2014 Analog 1 0322825 MLS005930026 2728458 173019996Synthesis 25.6 Apr. 15, 2014 Analog 2 0472782 MLS005939927 73050855173019979 Synthesis 24.7 Apr. 15, 2014 Analog 3 0472867 MLS00593992873050883 173019998 Synthesis 22.3 Apr. 15, 2014 Analog 4 0472866MLS005939929 73050881 173019997 Synthesis 22.8 Apr. 15, 2014 Analog 50472781 MLS005939930 73050862 173019978 Synthesis 21.5 Apr. 15, 2014

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

What is claimed is:
 1. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein L¹ is substitutedor unsubstituted C₂-C₆ alkylene, and R² is substituted or unsubstitutedheterocycloalkyl, where said heterocycloalkyl is not unsubstitutedmorpholine; R¹ is phenyl comprising a substituent group R^(1A); R^(1A)is —C(O)NR^(1C)R^(1D); R^(1C) is hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R^(1D) is substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; orR^(1C) and R^(1D) and the nitrogen atom they are attached to mayoptionally combine to form a substituted or unsubstitutedheterocycloalkyl; R³ is hydrogen, halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³,—OCX³ ₃, —OCHX³ ₂, —OCH₂X³, —CN, —SO_(n3)R¹⁶, —SO_(v3)NR¹³R¹⁴,—NHC(O)NR¹³R¹⁴, —N(O)_(m3), —NR¹³R¹⁴, —C(O)R¹⁵, —C(O)—OR¹⁵,—C(O)NR¹³R¹⁴, —OR¹⁶, —NR¹³SO₂R¹⁶, —NR¹³C(O)R¹⁵, —NR¹³C(O)OR¹⁵,—NR¹³OR¹⁵, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴ ishydrogen, halogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —OCX⁴ ₃, —OCHX⁴ ₂, —OCH₂X⁴,—CN, —SO_(n4)R²⁰, —SO_(v4)NR¹⁷R¹⁸, —NHC(O)NR¹⁷R¹⁸, —N(O)_(m4), —NR¹⁷R¹⁸,—C(O)R¹⁹, —C(O)—OR¹⁹, —C(O)NR¹⁷R¹⁸, —OR²⁰, —NR¹⁷SO₂R²⁰, —NR¹⁷C(O)R¹⁹,—NR¹⁷C(O)OR¹⁹, —NR¹⁷OR¹⁹, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵ ishydrogen, halogen, —CN, —SO_(n5)R²⁴, —SO_(v5)NR²¹R²², —NHC(O)NR²¹R²²,—N(O)_(m5), —NR²¹R²², —NR²¹SO₂R²⁴, —NR²¹C(O)R²³, —NR²¹C(O)OR²³,—NR²¹OR²³, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁶ is hydrogen, halogen, —CX⁶₃, —CHX⁶ ₂, —CH₂X⁶, —OCX⁶ ₃, —OCHX⁶ ₂, —OCH₂X⁶, —CN, —SO_(n6)R²⁸,—SO_(v6)NR²⁵R²⁶, —NHC(O)NR²⁵R²⁶, —N(O)_(m6), —NR²⁵R²⁶, —C(O)R²⁷,—C(O)—OR²⁷, —C(O) NR²⁵R²⁶, —OR²⁸, —NR²⁵SO₂R²⁸, —NR²⁵C(O)R²⁷,—NR²⁵C(O)OR²⁷, —NR²⁵OR²⁷ substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; eachR¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶,R²⁷ and R²⁸ is independently hydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂,—CH₂X, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; each X is independently —F,—Cl, —Br, or —I; each X³, X⁴, and X⁶ is independently —F, —Cl, —Br, or—I; each m3, m4, m5, and m6 is independently 1 or 2; each n3, n4, n5,and n6 is independently an integer from 0 to 3; and each v3, v4, v5, andv6 is independently 1 or
 2. 2. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein: L¹ is substituted orunsubstituted C₂-C₆ alkylene, and R² is unsubstituted heterocycloalkyl.3. The compound of claim 1, or a pharmaceutically acceptable salt,wherein: R^(1A) is para to the carbon attached to the quinazolinemoiety.
 4. The compound of claim 1, or a pharmaceutically acceptablesalt, wherein: R^(1C) is hydrogen or substituted or unsubstituted alkyl;and R^(1D) is substituted or unsubstituted alkyl.
 5. The compound ofclaim 1, or a pharmaceutically acceptable salt, wherein: R^(1C) andR^(1D) attached to the same nitrogen atom optionally combine to form asubstituted or unsubstituted heterocycloalkyl.
 6. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein: each of R³,R⁴, R⁵, and R⁶ is hydrogen.
 7. A pharmaceutical composition comprisingthe compound of claim 1 or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient.
 8. A method of treating adisease or condition, said method comprising administering to a subjectin need thereof an effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof, and wherein said disease orcondition is diabetes, heart disease, coronary artery disease,hyperlipidemia, lipodystrophy, insulin resistance, rheumatic disease,atherosclerosis, myocardial infarction, stroke, high blood pressure(hypertension), obesity, elevated fasting plasma glucose, high serumtriglycerides, elevated blood cholesterol, cardiac hypertrophy, heartfailure or metabolic syndrome.
 9. The method of claim 8, wherein saiddisease or condition is heart failure.
 10. The method of claim 9,wherein said heart failure is hypertrophy-induced heart failure.
 11. Themethod of claim 8, wherein said disease or condition is diabetes orhyperlipidemia.
 12. The method of claim 8, wherein said disease orcondition is metabolic syndrome.